Prof. Mohamed Elhasafi, Hepatoology Unit, Alexandria Faculty of Medicine.

COMPLICATIONS OF CIRRHOSIS

Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency

Variceal hemorrhage Ascites
Spontaneous bacterial peritonitis

Portal hypertension

Cirrhosis
Liver insufficiency Jaundice

Hepatorenal syndrome

Encephalopathy

Ascites is defined as the pathologic accumulation of fluid in the peritoneal cavity

Ascites is the most common complication

of cirrhosis, and 60% of patients with compensated cirrhosis develop ascites within 10 years during the course of their disease. The development of ascites in cirrhosis indicates a poor prognosis. The mortality is approximately 40% at 1 year and 50% at 2 years .

 The development of ascites is the final consequence of a

series of anatomic, pathophysiologic, and biochemical abnormalities occurring in patients with cirrhosis. The two older theories of ascites formation,fthe underfill theory and the overflow theory , appear to be relevant at different stages of the natural history of cirrhosis . The most recent theory, the arterial vasodilation hypothesis, appears to match best with the actual hemodynamic data, and has become the most widely accepted theory.

 The Peripheral Arterial Vasodilation Hypothesis considers that the primary event of renal sodium and water retention in cirrhosis is a splanchnic arterial vasodilation secondary to portal hypertension . At the initial phases of the disease, when ascites is still not present, circulatory homeostasis is maintained by the development of hyperdynamic circulation (high plasma volume, cardiac index and heart rate).

 However, as the disease progresses and splanchnic arterial vasodilation increases this compensatory

mechanism is insufficient to maintain circulatory homeostasis. Arterial pressure decreases, leading to stimulation of baroreceptors, homeostatic increase in the sympathetic nervous activity, renin-angiotensin system activity and circulating levels of ADH, and renal sodium and water retention .

NATURAL HISTORY OF ASCITES

Natural History of Ascites

Portal Hypertension No Ascites

HVPG <10 mmHg Mild Vasodilation

Uncomplicated Ascites

HVPG >10 mmHg Moderate Vasodilation

Refractory Ascites

HVPG >10 mmHg Severe Vasodilation

Hepatorenal Syndrome

HVPG >10 mmHg Extreme Vasodilation

CIRRHOSIS IS THE MOST COMMON CAUSE OF ASCITES

Cirrhosis is the Most Common Cause of Ascites

Peritoneal malignancy

Cirrhosis

Heart failure

Peritoneal tuberculosis
Others Pancreatic Budd-Chiari syndrome Nephrogenic ascites

Diagnosis of ascites
The initial evaluation of a patient with ascites should include history, physical examination, abdominal ultrasound, and laboratory assessment of liver function, renal function, serum and urine electrolytes, as well as an analysis of the ascitic fluid.

 Total ascitic fluid protein concentration

should be measured to assess the risk of SBP since patients with protein concentration lower than 1.5 g/dL have an increased risk of SBP.
A neutrophil count should be obtained to

rule out the existence of SBP.

Grading of ascites and suggested treatment.

Grade 1 ascites Mild ascites only detectable by ultrasound No
treatment.

Grade 2 ascites Moderate ascites evident by moderate

symmetrical distension of abdomen. Restriction of sodium intake and diuretics.

Grade 3 ascites Large or gross ascites with marked abdominal

distension. Large-volume paracentesis followed by restriction of sodium intake and diuretics (unless patients have refractory ascites).

Treatment of ascites
Bed rest : The assumption of an upright posture
associated with moderate physical exercise in patients with cirrhosis and ascites induces an intense stimulation of the renin-aldosterone and sympathetic nervous systems .

Sodium restriction : Mobilization of ascites occurs

when a negative sodium balance is achieved. This can be obtained simply by reducing the sodium intake to 6090mEq/day .

 Fluid restriction

Is not a necessity when treating most patients with cirrhotic ascites.

Diuretics In contrast to what occurs in healthy subjects in

whom furosemide is more potent than spironolactone, in cirrhotic patients with ascites spironolactone is more effective than furosemide. Most cirrhotic patients with ascites respond to spironolactone. The simultaneous administration of furosemide and spironolactone increases the natriuretic effect of both agents and reduces the incidence of hypo or hyperkalemia that may be observed when these drugs are given alone.

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

 The good oral bioavailability of furosemide in the patient

with cirrhosis, together with the acute reduction in glomerular filtration rate associated with intravenous furosemide , favor the use of the oral administration.

The maximum recommended weight loss during diuretic therapy should be 0.5 kg/day in patients

without edema and 1 kg/day in patients with edema. The goal of long-term treatment is to maintain patients free of ascites with the minimum dose of diuretics.

 Caution should be used when starting treatment with

diuretics in patients with renal impairment, hyponatremia, or disturbances in serum potassium and patients should be submitted to frequent clinical and biochemical monitoring. Diuretics are generally contraindicated in patients with overt hepatic encephalopathy.

All diuretics should be discontinued if there is severe hyponatremia (serum sodium concentration <120

mmol/L), progressive renal failure, worsening hepatic encephalopathy, or incapacitating muscle cramps.

REFRACTORY ASCITES
Ascites that is nonresponsive to sodium-

restricted diet and high- dose diuretic treatment ( 400 mg/ d spironolactone and 160 mg/ d furesemid), in the absence of prostaglandin inhibitors, such as NSAIDs.

Management of refractory ascites :

1) Serial therapeutic paracentesis. 2) Peritoneovenous shunt. 3) Transjugular intrahepatic portosystemic stent- shunt. 4) Liver transplantation.

 Large-volume paracentesis (LVP) is the first-line therapy in

patients with large ascites (grade 3 ascites). LVP should be completed in a single session. LVP should be performed together with the administration of albumin (8 g/L of ascitic fluid removed) to prevent circulatory dysfunction after LVP. In patients undergoing LVP of less than 5 L of ascites, the risk of developing post-paracentesis circulatory dysfunction is low. After LVP, patients should receive the minimum dose of diuretics necessary to prevent the re-accumulation of ascites.

 Non-steroidal anti-inflammatory drugs (NSAIDs) are

contraindicated in patients with ascites because of the high risk of developing further sodium retention, hyponatremia, and renal failure. Drugs that decrease arterial pressure or renal blood flow such as ACE-inhibitors, angiotensin II antagonists, or a1adrenergic receptor blockers should generally not be used in patients with ascites because of increased risk of renal impairment.

PERITONEOVENOUS SHUNT:
Le Veen or Denever shunts were popularized in the 1970s as a physiologic treatment of ascites . However, poor long term patency, excessive complications and no survival advantages compared to medical therapy have led to near abandonment of this procedure.

Use of jugular vein will hinder TIPS placement

One-way valve

Intraabdominal adhesions may complicate liver transplant surgery

Transjugular intrahepatic portosystemic shunts (TIPS):

TIPS is the most recent treatment introduced for the management of portal hypertension. It works as a side-to-side portacaval shunt. TIPS should be considered in patients with very frequent requirement of large-volume paracentesis, or in those in whom paracentesis is ineffective (e.g. due to the presence of loculated ascites). TIPS is extremely effective in improving circulatory and renal function and in the management of ascites. TIPS is effective in the management of refractory ascites but is associated with a high risk of hepatic encephalopathy.

(DOI:10.1016/j.cgh.2011.06.013 ) Copyright 2011 AGA Institute

LIVER TRANSPLANTATION
Liver transplantation should be

considered in the treatment options of patients with refractory ascites. Once patient become refractory to routine medical therapy, 50% die within 6 months. The 12-month survival of patients with refractory ascites is only 25%.

Hepatic hydrothorax
Hepatic hydrothorax is defined as a pleural effusion (>500

mL) in patients with cirrhosis without coexisting cardiopulmonary diseases. It is a manifestation of decompensated chronic liver disease. Although the exact mechanisms involved in the development of hepatic hydrothorax have not been welldefined, several observations indicate that the most likely cause is passage of a large amount of ascites from the peritoneal to the pleural cavity through diaphragmatic defects.

 The negative intrathoracic pressure favours the transfer of

fluid across these defects and hence patients usually have mild ascites. In most cases (85%) hepatic hydrothorax develops on the right side with 13% of cases occurring on the left side and 2% being bilateral. Patients who are severely symptomatic should undergo a therapeutic thoracentesis followed by a sodium restricted diet and diuretics. Less symptomatic patients can be treated initially with sodium restriction and diuretics.

 Options for patients who are refractory to sodium

restriction and diuretics include serial thoracentesis, transjugular intrahepatic portosystemic shunt (TIPS) placement, pleurodesis, and thoracoscopic surgery. Chest tubes should not be placed. Placement of chest tubes in patients with hepatic hydrothorax can result in massive protein and electrolyte depletion, infection, renal failure, and bleeding . Furthermore, once it has been inserted, it may be impossible to remove the tube because of the continuous reaccumulation of fluid.

Spontaneous bacterial peritonitis

Infection of ascites characteristic of the cirrhotic patient

that occurs in the absence of a contiguous source of infection ( e.g. intestinal perforation, intra-abdominal abscess ) and in the absence of an intra-abdominal inflammatory focus such as an abscess , acute pancreatitis, or cholecystitis. A diagnostic paracentesis should be carried out in all patients with cirrhosis and ascites at hospital admission to rule out SBP.

Spontaneous Bacterial Peritonitis

Polymorphonuclear leukocytes > 250 /mL
Positive ascites culture (in blood culture bottles) Absent intra-abdominal source of infection requiring surgery

MICROORGANISMS ISOLATED IN SPONTANEOUS BACTERIAL PERITONITIS (SBP)

Microorganisms Isolated in Spontaneous Bacterial Peritonitis

Microorganism Gram-negative bacilli
Escherichia coli Klebsiella spp Other

% of Cases 72
47 13 13

Gram-positive cocci
Streptococcus spp S. pneumoniae Other streptococci Enterococcus sp Staphylococcus sp

29
19 7 12 5 4

Anaerobes and microaerophils Miscellaneous

5 2

 Ascitic fluid culture is frequently negative even

if performed in blood culture bottles and is not necessary for the diagnosis of SBP, but it is important to guide antibiotic therapy. Some patients may have an ascitic neutrophil count less than 250/mm3 but with a positive ascitic fluid culture. This condition is known as bacterascites.

 Third-generation cephalosporins.

Cefotaxime minimal dose 2 grams IV every 12 hours for a minimal duration of 5 days - Alternatives: Ceftizoxime, Ceftriaxone, Ceftazidine, Amoxicillin-Clavulanic acid - If patient has beta-lactam hypersensitivity Quinolones (e.g. Ciprofloxacin)

Albumin - Albumin infusion-dose of 1.5 grams/kg body weight within 6 hours of SBP diagnosis followed by 1 gram/kg BW on day 3 - Albumin reduced mortality (29% to 10%)

 Spontaneous bacterial empyema should be managed

similarly as SBP. HRS occurs in approximately 30% of patients with SBP treated with antibiotics alone, and is associated with a poor survival. The administration of albumin (1.5 g/kg at diagnosis and 1g/kg on day 3) decreases the frequency of HRS and improves survival.

Indications for Prophylactic Antibiotics to Prevent Spontaneous Bacterial Peritonitis

Cirrhotic patients hospitalized with GI hemorrhage (short-term)
Norfloxacin 400 mg p.o. BID x 7 days

Patients who have recovered from SBP (longterm)

Norfloxacin 400 mg p.o. daily, indefinitely Weekly quinolones not recommended (lower efficacy, development of quinolone-resistance)

Hepatorenal syndrome
Hepatorenal syndrome (HRS) is defined as

the occurrence of renal failure in a patient with advanced liver disease in an absence of identifiable cause of renal failure. Thus, the diagnosis is essentially one of exclusion of other causes of renal failure.

Criteria for diagnosis of hepatorenal syndrome in cirrhosis:

Cirrhosis with ascites Serum creatinine >1.5 mg/dl . Absence of shock Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <1.5mg/dL) following at least 2 days of diuretic withdrawal (if on diuretics), and volume expansion with albumin at 1 g/kg/day up to a maximum of 100 g/day. No current or recent treatment with nephrotoxic drugs. Absence of parenchymal renal disease as defined by proteinuria <0.5 g/day, no microhaematuria (<50 red cells/high powered field), and normal renal ultrasonography.

URINE SODIUM AND URINE VOLUME ARE MINOR CRITERIA IN THE DIAGNOSIS OF HEPATORENAL SYNDROME (HRS)

Minor criteria
Urine sodium <10 mEq/L Urine osmolality > plasma osmolality Serum sodium < 130 mEq/L Urine volume < 500 ml/day Urine RBCs < 50/HPF

Arroyo et al., Hepatology 1996; 23:164

Classification
Type 1 - rapidly progressive, oliguria, very low urine
Na, hyponatremia, precipitating event (SBP or other bacterial infection, surgery, GI bleed)

see death within 2-3 weeks dialysis is unhelpful unless transplantation planned

Type 2 - moderate renal insufficiency (Cr 1.5-2.5

mg/dl), steady for months, can progress into Type 1 with precipitant.

Pathogenesis of Type 2 HRS and Type 1 HRS

ADVANCED LIVER DISEASE AND SEVERE PORTAL HYPERTENSION SEVERE CIRCULATORY DYSFUNCTION AND RENAL HYPOPERFUSION

SEVERE SPLANCHNIC ARTERIAL VASODILATION

CARDIAC DYSFUNCTION

ACUTE IMPARIMENT OF CIRCULATORY FUNCTION (i.e. SBP)

MARKED ACTIVATION OF SNS, RAAS AND ADH

RENAL ISCHEMIA
Increased intrarenal vasodilators

MODERATE AND STEADY RENAL VASOCONSTRICTION

INTRARENAL VASODILATORS

INTRARENAL VASOCONSTRICTORS

TYPE 2 HRS
.

TYPE 1 HRS

Treatment of HRS
Ameliorate renal vasocontriction by:

Reducing
TIPS

splanchnic blood flow

IV

albumin Splanchnic vasoconstrictors Terlipressin (V-1 agonist) Midodrine (-1 agonist) Somatostatin (octreotide)

Terlipression
Long-acting vasopressin analogue
Stimulates splanchnic V1 vasopressin receptors Increases: Arterial blood pressure GFR Urine volume Terlipressin (1 mg/46 h intravenous bolus) in combination with albumin should be considered the first line therapeutic agent for type 1 HRS.

 If serum creatinine does not decrease at least 25% after 3

days, the dose of terlipressin should be increased in a stepwise manner up to a maximum of 2 mg/4 h. For patients with partial response (serum creatinine does not decrease <1.5 mg/dL) or in those patients without reduction of serum creatinine treatment should be discontinued within 14 days.
Contraindications to terlipressin therapy include ischemic

cardiovascular diseases. Patients on terlipressin should be carefully monitored for development of cardiac arrhythmias or signs of splanchnic or digital ischemia, and fluid overload, and treatment modified or stopped accordingly.

 Potential alternative therapies to terlipressin include norepinephrine or midodrine plus octreotide, both in

association with albumin.

Management of type 2 hepatorenal syndrome:

Terlipressin plus albumin is effective in 6070% of patients with type 2 HRS.

There are insufficient data on the impact of this

treatment on clinical outcomes.

Liver transplantation:
Liver transplantation is the best treatment for

both type 1 and type 2 HRS. HRS should be treated before liver transplantation, since this may improve postliver transplant outcome