• Typically defined as a widened alveolar-arterial oxygen gradient (A-a pO2) on room air (>15 mmHg, or >20 mmHg in patients >64 years of age) with or without hypoxemia resulting from intrapulmonary vasodilatation in the presence of hepatic dysfunction or portal hypertension.
• The hallmark of HPS is intrapulmonary vasodilatation of the precapillary and capillary vessels, impairing arterial oxygenation. A few pleural and pulmonary arteriovenous communications (shunts) and portopulmonary venous anastomosis are common findings as well.

Other key points

• Incidence is 15 to 20% in those with cirrhosis
• Can co exist with other cardiopulmonary abnormalities.
• A pO2 <70 mmHg is useful for clinically identifying those with significant HPS.
• There is no relationship between the presence or severity of the HPS and the severity of liver disease.
• Severity of hypoxemia appears to be directly related to the extent of intrapulmonary shunt, diffusion-perfusion impairment, or both.

Pathogenesis: current concepts

• Excessive vascular production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) causing vasodilatation.
• Other mediators may contribute to vascular tone i.e. heme oxygenase 1
• Hepatic endothelin-1 (ET-1) appears to be an important mechanism for triggering the increase in pulmonary eNOS and the onset of vasodilatation.
• Progression of HPS results in accumulation of macrophages in the pulmonary microvasculature, which produce inducible NOS & heme oxygenase 1. They respectively release NO and CO, causing further vasodilatation.
• TNF-a contributes to macrophage accumulation.

Clinical manifestations

• Insidious onset of exertional dyspnoea.
• Platypnea: shortness of breath exacerbated by sitting up and improved by lying supine.
• Orthodeoxia: hypoxemia exacerbated by going from supine to a upright position.
• Pulmonary AVMs are predominantly situated at the lung bases. Hence, dependent blood pooling occurs on sitting/standing with subsequent increased AV shunting.
• Clubbing, cyanosis and spider naevi in the presence of liver disease/portal hypertension should raise the suspicion of HPS.

Diagnosis

• Triad
  • Of liver disease or portal hypertension
  • Of intrapulmonary vasodilatation
  • Elevated age adjusted A-a pO2 gradient: [0.26age -0.43] + 10

Investigations

• ABG
  • Performed when SpO2 <97% or if history and exam strongly suggests HPS.
• CXR and pulmonary function tests to assess for other pulmonary disorders i.e. hepatic hydrothorax, COPD, pulmonary fibrosis.
• Transthoracic microbubble contrast ECHO
  • The left ventricle opacifies at least three cardiac cycles after the right (delayed shunting). Microbubbles do not pass through normal capillaries. This intrapulmonary shunting is characteristic of HPS.
• Macroaggregated albumin scan
  • This is useful to determine the contribution of HPS in patients with both intrapulmonary vasodilatation and intrinsic cardiopulmonary disease. Radiolabelled albumin macroaggregates (20um) are infused into the venous circulation. In significant intrapulmonary shunting, a fraction of the macroaggregates pass from the lungs into the systemic circulation. Normally, these particles would become trapped in the pulmonary microvasculature.
• Pulmonary function tests
  • Abnormal findings are of low specificity.
  • TLC and expiratory flow rates are generally normal in HPS.
  • Diffusion impairment for CO is common in HPS.
• Pulmonary angiography
  • Low sensitivity for detecting intrapulmonary vasodilatation. Should only be performed when pO2 <60mmHg which is poorly responsive to oxygen administration and when there is a strong suspicion of direct AV communications that may be amenable to embolisation.
• High resolution CT
  • Some evidence that quantitation of intrapulmonary vasodilatation is possible

Natural history/prognosis

• The natural history has yet to be fully established but most patients with HPS appear to have progressive intrapulmonary vasodilatation with worsening gas exchange.
• Reported median survival of 24 months and a 5-year survival rate of 23% in those not suitable for OLT.
• Survival and mortality rates are worse for patients with HPS, even after adjustment for the Child Turcotte Pugh classification of liver disease.
• Death is often due to hepatic complications rather than respiratory.

Treatment

• Orthotopic liver transplant is the only effective treatment for HPS. HPS with a pO2 <60mmHg is considered to be an indication for OLT. However, it may take up to a year post transplant for arterial hypoxaemia to normalise.
• Long term oxygen therapy is mainstay treatment for those with pO2 <60mmHg or exertional induced hypoxaemia.
• The role of TIPSS is uncertain and there are no established medical therapies.

Degree of severity

• Mild: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?80 mm Hg
• Moderate: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?60 to <80 mm Hg
• Severe: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen ?50 to <60 mm Hg
• Very severe: Alveolar–arterial oxygen gradient ?15 mm Hg, partial pressure of oxygen <50 mm Hg (<300 mm Hg while the patient is breathing 100% oxygen).

References
1.Hepatopulmonary Syndrome — A Liver-Induced Lung Vascular Disorder. Rodríguez-Roisin R, Krowka MJ, N Engl J Med 2008 May; 358:2378-2387.

2.The hepatopulmonary syndrome. Palma DT, Fallon MB. J Hepatol. 2006 Oct;45(4):617-25.

HE may be defined as a disturbance in central nervous system function because of hepatic insufficiency. It can be present in both acute and chronic liver failure. The neuropsychiatric manifestations are reversible.

Discuss the pathophysiology of HE?

• A large body of work points at ammonia as a key factor in the pathogenesis of HE.
• Portal ammonia is derived from both the urease activity of colonic bacteria and the deamidation of glutamine in the small bowel.
• The intact liver clears almost all of the portal vein ammonia, converting it into glutamine and preventing entry into the systemic circulation.
• Ammonia gain access to the systemic circulation as a result of decreased hepatic function or portal-systemic shunts.
• Once in brain tissue, they produce alterations of neurotransmission that affect consciousness and behaviour.
• In acute and chronic liver disease, increased arterial levels of ammonia are commonly seen. However, correlation of blood levels with mental state in cirrhosis is inaccurate.

Discuss the clinical presentation of HE?

• HE is a diagnosis of exclusion. Other metabolic and cerebral structural causes can have a similar presentation.
• Pre existing liver disease (acute or chronic), presence of a precipitating factor, and/or a prior history of HE are clinical elements needed for diagnosis.
• Measurement of venous ammonia blood levels may be helpful
• The most distinctive presentation is the development of an acute confusional state that can evolve into coma (acute encephalopathy).

Discuss the stages of HE?
West Haven criteria:
Stage 0. Lack of detectable changes in personality or behaviour. Asterixis absent.
Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or
depression. Asterixis can be detected.
Stage 2. Lethargy or apathy. Disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis.
Stage 3. Gross disorientation. Bizarre behaviour. Semistupor to stupor. Asterixis generally absent.
Stage 4. Coma.

Discuss the management of HE?

Nutrition

In case of deep encephalopathy, oral intake is withheld for 24–48 h and i.v. glucose is provided until improvement. Enteral nutrition can be started if the patient appears unable to eat after this period. Protein intake begins at a dose of 0.5 g/kg/day, with progressive increase to 1–1.5 g/kg/day.

Precipitating factors

A precipitating factor can be found in most cases of cirrhosis with acute or chronic HE. These factors should be vigorously searched and eliminated. The precipitating factors are:

• GI bleed
• Infections- SBP or any other infection.
• Renal and electrolyte disturbances- renal failure, metabolic alkalosis, hypokalaemia, dehydration, and diuretic effects.
• Medication- benzodiazepines, narcotics, and other sedatives.
• Constipation
• Excessive dietary protein.
• Acute deterioration of liver function in cirrhosis- like superimposed alcoholic hepatitis, portal vein thrombosis etc.

Lactulose is a first-line pharmacological treatment of HE.

• Lactulose (galactosido-fructose) is not broken down by intestinal disaccharidases and thus reaches the colon, where bacteria will metabolize the lactulose to acetic acid and lactic acid. This lowers the colonic pH and thus favours the formation of the nonabsorbable NH4+ from NH3, trapping NH3 in the colon and effectively reducing plasma ammonia concentrations. Other effects like catharsis also contribute to the clinical effectiveness of lactulose.
• An excessively sweet taste, flatulence, and abdominal cramping are the most frequent subjective complaints with this drug.
• For acute encephalopathy, lactulose (ingested or via nasogastric tube), 45 ml p.o., is followed by dosing every hour until evacuation occurs. Then dosing is adjusted to an objective of two to three soft bowel movements per day (generally 15–45 ml every 8–12 h).
• Lactitol is more palatable and can be used instead of lactulose. Both are equally efficacious.

Enemas
Bowel cleansing is a rapid and effective method to remove ammoniagenic substrates.

Antibiotics
The goal of antibiotic therapy in the treatment of HE is to reduce the mass o f enteric bacteria that produce ammonia. Antibiotics are reserved for patients who respond poorly to disaccharides. So antibiotics are added to lactulose after 48 hours, if the response has been poor. Options are

• Neomycin (1-2 g/day) – concerns regarding oto and nephro toxicity limits its use.
• Metronidazole (250 mg bd) – neurotoxicity limits its use
• Rifaximin (400 mg t.i.d) is much better tolerated, but is expensive. The tolerability pro?le of rifaximin is comparable to placebo

Liver transplantation

The development of overt HE carries a poor prognosis with a 1-yr survival of 40%. Appropriate candidates should be referred to transplant centres after the first episode of overt encephalopathy of any type.

Ref
Blei AT, Córdoba J. Hepatic Encephalopathy. Am J Gastroenterol. 2001 Jul; 96(7):1968-76.
http://www.gi.org/physicians/guidelines/HepaticEncephalopathy.pdf

Portal venous pressure is determined by the product of portal venous flow and the resistance to outflow from the portal venous system:

Portal pressure = Portal venous flow x portal venous outflow resistance

It is usually caused by an increase in resistance in the portal-hepatic vascular bed due to obstruction to flow, which in the vast majority of patients is related to cirrhosis.

However, a variety of disorders can cause portal hypertension in the absence of cirrhosis, a condition referred to as “noncirrhotic portal hypertension.”

In both the above cases the PH is because of increased resistance, but rarely PH can result because of increased portal flow in normal resistance, e.g. splanchnic AF fistula

Discuss portal vein anatomy?

• Splenic vein joins with short gastric vessels to form the main Splenic vein
• Inferior mesenteric vein joins Splenic vein in its medial third and left gastric vein joins the confluence of Splenic vein and SMV
• Splenic vein joins the superior mesenteric vein to form the portal vein
• portal vein bifurcates into right and left branches
• umbilical vein joins the bifurcation of the above
• Portal blood flow is 1200ml/mt and it carries 72% of the oxygen content of the liver and the 75% of the total blood flow ( hepatic artery carries 400ml/mt = 25%)

Discuss the normal pressure and flows?

Hepatic vein pressure= 4mm Hg
Portal vein pressure= 7mm Hg
Hepatic artery pressure = 100 mm Hg

Hepatic vein flow = 1600ml/mt
Portal vein flow = 1200ml/mt
Hepatic artery flow = 400ml/mt

Portal pressure is 7 mm Hg (remember this is an average value – but absolute in nature rather than below)
Portal hypertension is defined by a hepatic venous pressure gradient (HVPG) greater than 5 mmHg.

When the portal circulation is obstructed, whether it is within or outside the liver, a remarkable collateral circulation develops to carry portal blood into the systemic circulation veins.

Collaterals usually imply PH although occasionally if the collateral circulation is very extensive portal pressure may fall.
Conversely PH of short duration can exist without a demonstrable collateral circulation

Haemodynamic of PH
Normally 100% of portal blood flow is recoverable from hepatic veins whereas in cirrhosis only 13% goes to hepatic vein and rest reaches the systemic circulation through the collaterals
Discuss portal pressure studies?

• A balloon catheter is introduced into femoral or internal jugular vein under fluoroscopic control
• first catheter tip is wedged into a tributary of hepatic vein and balloon is inflated = Wedged hepatic venous pressure= WHVP
• Then it is withdrawn into the hepatic vein = Free Hepatic Venous Pressure= FHVP
• Normal uncorrected portal pressure is 5-10mm Hg and is influenced by the intra-abdominal pressure and central venous filling pressure.
• In order to eliminate the contribution of intra-abdominal pressure and central venous pressure and thus express portal pressure as the intrinsic pressure difference between the portal and systemic venous compartments portal pressure is usually expressed as a portal pressure gradient
• So Hepatic Venous Pressure Gradient = HVPG= WHVP- FHVP= 7-4=3
• PH is defined as HVPG > 5
• Risk of GIB when HVPG > 12

Discuss the causes of portal hypertension?

Causes of presinusoidal portal hypertension – associated with relatively normal hepatocellular function and consequently if patient suffers a haemorrhage from varices liver failure is rarely a consequence in contrast patients with the intra-hepatic type frequently develop liver failure after bleeding

• Extrahepatic portal vein obstruction – Particularly prominent gastric varices – supplied by short gastric veins
• Lesions in surrounding structures: pancreatitis, tumour, biliary tract disease
• Lesions of vessel wall: phlebitis-pylephlebitis, omphalitis
• Hypercoagulable state
• Segmental portal hypertension
• Intrahepatic portal vein obstruction
• Schistosomiasis- later mixed presinusoidal and sinusoidal
• Noncirrhotic portal fibrosis
• Early Primary biliary cirrhosis – later mixed presinusoidal and sinusoidal
• Early Sclerosing cholangitis – early – later mixed presinusoidal and sinusoidal
• Sarcoidosis
• Myeloproliferative disease- later mixed presinusoidal and sinusoidal
• Congenital hepatic fibrosis
• Hepatic arterioportal fistula
• Non Obstructive causes – increased blood flow
• Splanchnic arteriovenous fistula
• Idiopathic tropical splenomegaly – Splenomegaly may cause portal hypertension because of hyperdynamic portal blood flow arising from the enlarged spleen.
• Splenomegaly (eg, lymphoma, Gaucher’s disease)

Causes of Sinusoidal portal hypertension

• Cirrhosis – secondary to chronic hepatitis
• Noncirrhotic cause
• Acute hepatitis – alcoholic hepatitis
• FHF
• Vitamin A toxicity
• Arsenic poisoning – both pre-sinusoidal and sinusoidal
• Vinyl chloride toxicity – both pre-sinusoidal and sinusoidal
• Secondary syphilis
• Nodular regenerative hyperplasia

Causes of post sinusoidal portal hypertension

• Intra-hepatic
• Venoocclusive disease (VOD)
• Budd-Chiari syndrome (hepatic vein thrombosis)

• Extra-hepatic
• IVC obstruction- web/thrombus
• Constrictive pericarditis
• Restrictive cardiomyopathy
• Tricuspid regurgitation
• Severe right heart failure

Discuss the mechanism of increased resistance in sinusoidal portal hypertension?

• Hepatocyte swelling
• Collagen deposition in space of Disse
• Loss of intersinusoidal anastomoses
• Compression by regenerative nodules and fibrosis

As a general rule, the clinical consequences of portal hypertension are similar regardless of the cause or site of obstruction. However, several pathophysiologic changes are related to specific types and causes of portal hypertension, which may influence their clinical presentation and therapy.

Liver Cirrhosis: pic shows destruction and fibrosis in centre, with remaining nodules of more normal liver at bottom right and top left. Note the irregular whorls of fibrosis around the nodules.

• Non selective beta-blockers (propanolol, nadolol) prevent bleeding in more than half of patients with large varices) by reducing portal pressure by decreasing cardiac output) and, more importantly, by producing splanchnic vasoconstriction, thereby reducing portal blood flow. Selective beta-blockers (atenolol, metoprolol) are less effective and are suboptimal for primary prophylaxis of variceal haemorrhage. 1 bleeding episode is avoided for every 10 patients treated with beta-blockers. Propanolol is usually started at a dose of 20 mg twice a day (BID) and Nadolol is usually started at a dose of 40 mg once a day and) is adjusted to maximal tolerated doses. The most common side effects related to beta-blockers in cirrhosis are light headedness, fatigue, and shortness of breath. Some of these side effects disappear with time or after dose reduction.
• EVL can be considered for primary prophylaxis in patients with contraindications or intolerance or non-compliance to beta -blockers.  If a patient is treated with EVL, it should be repeated every 1-2 weeks until obliteration with the first surveillance OGD performed 1-3 months after obliteration and then every 6-12 months to check for variceal recurrence.
• Nitrates (either alone or in combination with beta-blockers), shunt therapy, or sclerotherapy should not be used in the primary prophylaxis of variceal haemorrhage

Where would you consider primary prophylaxis?

• In patients with cirrhosis and small varices that have not bled but have criteria for increased risk of haemorrhage (Child B/C or presence of red wale marks on varices), nonselective beta-blockers should be used for the prevention of first variceal haemorrhage
• In patients with medium/large varices that have not bled but have a high risk of haemorrhage (Child B/C or variceal red wale markings on endoscopy), non selective beta-blockers or EVL may be recommended for the prevention of first variceal haemorrhage.
• In patients with medium/large varices that have not bled and are not at the highest risk of haemorrhage (Child A patients and no red signs), nonselective beta-blockers (propanolol, nadolol) are preferred and EVL should be considered in patients with contraindications or intolerance or non-compliance to beta-blockers.

Discuss management of acute variceal bleed?

• Resuscitation- aim for a haemoglobin of approximately 8 g/dL. This is based on experimental studies that show that restitution of all lost blood leads to increases in portal pressure to levels higher than baseline, and to more rebleeding and mortality.
• Pre endoscopic treatment- Terlipressin should be given to patients suspected of variceal haemorrhage.  A RCT showed that bleeding control was significantly better with terlipressin compared with the placebo group. Mortality due to bleeding episodes was significantly lower in the terlipressin group at day 15 but this effect was not maintained over the loner time scale. Two RCTs showed that somatostatin use did not cause reduced rebleeding or mortality. One of these trial showed an improvement in the rate of haemostasis with somatostatin. There are no trails for the pre endoscopic use of octreotide
• Early Endoscopy (within 12-24 hrs) after resuscitation. Variceal band ligation therapy is superior to sclerotherapy in terms of rebleeding, all cause mortality and death due to bleeding in patients with bleeding oesophageal varices.
• Post endoscopic therapy-After endoscopic treatment of oesophageal variceal haemorrhage patients should receive vasoactive drug treatment (terlipressin for 48 hrs, octreotide or high dose somatostatin each for 3-5 days). Combination therapy (endoscopic treatment plus vasoactive drugs) has been shown to be superior in terms of better haemostasis and reduced early rebleeding rates. There is no survival benefit.  (NB- High dose somatostatin- 500mcg bolus followed by 500 mcg/hr, octreotide- 50 mcg bolus followed by 25-50 mcg/hr, Terlipressin- 1-2 mg IV 4-6 hrly)
• Antibiotic therapy (ceftriaxone 1gm/day or ciprofloxacin 400 mg BD- maximum 7 days) should be commenced in patients with chronic liver disease who present with upper GI bleed. Antibiotic use significantly reduces mortality in this group of patients.

Discuss management of bleeding varices not controlled by endoscopy?
These patients should be managed in two stages:

• Initial emergency therapy to arrest blood loss- balloon tamponade achieves haemostasis in 80-95% of patients with either oesophageal or gastric varices. (complications of balloon tamponade- oesophageal tear, pneumonia and discomfort)
• Second line therapy to treat the underlying cause- TIPS is considered the therapy of choice.

Discuss prevention of variceal bleed?

Recurrence of variceal bleed can be as high as 80% within a year.

• Variceal band ligation (EVL) combined with a beta blocker (propanolol or nadolol) is recommended for secondary prevention for oesophageal variceal haemorrhage (most trials use propanolol 160 mg LA OD). EVL should be repeated every 1-2 weeks until obliteration with the first surveillance EGD performed 1-3 months after obliteration and then every 6-12 months to check for variceal recurrence.
• In patients unsuitable for variceal band ligation combination of non selective beta blocker and nitrates (ISMN- 20mg BD and increased to 40 mg BD) is recommended for secondary prevention of oesophageal variceal haemorrhage.
• TIPS should be considered to prevent oesophageal rebleeding in patients with contraindications, intolerance to or failure of endoscopic and/or pharmacological therapy.

Discuss gastric varices?
Types
Gastro-oesophageal (GOV) Type 1- these gastric varices are in continuity with oesophageal varices extending less than 5 cms along the lesser curve of the stomach.
GOV type 2- those which are in continuity with oesophageal varices but which extend further towards the fundus.

Isolated gastric varices (IGV) – are classified according to whether they are found in the fundus (IGV type 1) or elsewhere in the stomach (IGV type 2)

Management

• Patients with confirmed gastric variceal bleed should have endoscopic therapy preferably with cyanoacrylate injection. A retrospective study suggested that cyanoacrylate was more cost effective than TIPS. There were no significant differences in mortality or rebleeding between the two treatments. Most patients had GOV type 1 varices.
• Prevention of rebleed- there are no placebo controlled studies to examine the efficacy of beta blockers in preventing rebleeding in gastric varices. TIPS should be considered to prevent gastric variceal rebleed.

Pic 1 Oesophageal varices

Pic 2 Gastric varices

Pic 3 Banded oesophageal varices

Ref

1. British Society of Gastroenterology guidelines on the Management of Variceal Haemorrhage in Cirrhotic Patients.
2. http://www.sign.ac.uk/guidelines/fulltext/105/index.html (Adopted by BSG)
3. AASLD Practice Guidelines. Prevention and Management of Gastroesophageal Varices and Variceal Haemorrhage in Cirrhosis.

• Portal hypertension leads to intestinal oedema and sluggish movement leading to bacterial overgrowth.
• This leads to bacterial translocation in presence of increased capillary permeability.
• The bacteria seed the mesenteric lymph nodes and then it goes to lymphatic or to systemic circulation and ultimately comes to ascitic fluid.
• The bacteria cannot be phagocytosed by local macrophages and neutrophil because of lack of opsonisation caused by low complement levels in cirrhotic patients. (Ascitic fluid <10gm/L indicates high chance of having SBP)

What is SBP?

• Monomicrobial infection of ascitic fluid in absence of contagious source of sepsis.
• It is confirmed by positive bacterial culture of the ascitic fluid and ascitic fluid neutrophil count of >250cells/mm3
• Occurs in the background of advanced cirrhosis, particularly when ascitic fluid protein goes below 10gm/L
• Usual source is gut bacteria but may be secondary to bacteraemia from UTI/ dental abscess/ cellulites etc

What is secondary bacterial peritonitis?

• Polymicrobial infection of ascitic fluid in presence of surgically treatable source of sepsis.
• It is confirmed by positive bacterial culture of the ascitic fluid and ascitic fluid neutrophil count of >250cells/mm3 (in contrast to SBP neutrophil count is normally >1000cells/mm3)
• Two types: perforation peritonitis- rupture of bowel/stomach and non perforation peritonitis – perinephric abscess

Discuss the incidence and prognosis of SBP?
SBP occurs in 10-30% of cirrhotic hospitalised patients

Untreated mortality is 90% which is reduced to 20% with early diagnosis and prompt treatment.

When to suspect SBP?

Any cirrhotic ascites on admission to hospital for any reason should have a diagnostic tap.

Any known cirrhotic with ascites with fever, abdominal pain, confusion, encephalopathy, abdominal tenderness or diarrhoea or developing renal failure should have diagnostic tap.

Risk factors for SBP in cirrhotic:

Low ascitic fluid protein
On PPI
Malnutrition
GI bleeding

Does it matter if fluid is sent in EDTA bottle or normal bottle for cell count?

Yes. The sample if clotted will give a false negative result if sent in a white top universal container.

How to diagnose by ascitic fluid analysis?

• Send EDTA sample 1ml for cell type and differential count- ask lab to bleep with the result
• Normally done by on call microbiology technician rather than automated coulter counter which can be inaccurate in this low level of neutrocytois ( 0.25×109 /L in ascitic fluid as opposed to normal blood WBC of 10×109 /L)
• A neutrophil count of >250 cells/mm3 is confirmatory.

Does it matter if fluid is sent in blood culture bottle or normal bottle?

Yes, inoculation at bed side in blood culture bottle will yield positive culture in 72-90% of cases of SBP as opposed to only 40% if culture is sent in white topped sterile universal container (which is the common practice)

Is Gram stain necessary?

Rarely helpful in SBP and BSG does not recommend requesting it.

What is bacterascites?

Ascitic fluid which is culture positive but with normal neutrophil count.

What is CNNA?

Culture negative neutrocytic ascites should be treated exactly as SBP as they have similar morbidity and mortality.

Do they need repeat tap to make sure the count is improving?

If repeat tap after 48hrs does not show reduction in the neutrophil count to >25% of the pre-treatment value – implies treatment failure. Antibiotic should be changed. This is important particularly if patient is still symptomatic and not improving.
Why it is important to differentiate SBP from secondary BP?

The patients of secondary BP will die almost 100% in spite of antibiotic in absence of surgery

The patients of SBP will have 80% mortality if they have unnecessary laparotomy.

How to differentiate from secondary BP?

Neutrophil count: normally in hundreds in SBP and in thousands in Secondary BP

Sugar: <2.8 mmol/L in Secondary BP because high numbers of neutrophil consume sugar and in frank perforation sugar level can be zero

Protein: low (<10g/L) in SBP, higher in Secondary BP
LDH: High in secondary BP greater than the upper limit of normal for serum

Microbial flora on culture/Gram stain: polymicrobial in secondary BP. Gram stain is normally negative in SBP and shows polymicrobial flora in secondary BP. Even then Gram stain is not recommended.

CEA: High levels in secondary BP
ALP: High levels in secondary BP

Also Erect CXR shows gas under diaphragm/ gastrograffin enema shows extravasation of contrast into the peritoneum.

What are the differentials of Secondary BP?

Late presentation of SBP, SBP treated with resistant antibiotic, peritoneal carcinomatosis and tubercular peritonitis can masquerade as secondary BP with very high WBC count and low ascitic fluid sugar and high LDH.

What is the microbiological flora?

In 70% of cases it is – either E.Coli, Streptococcus or enterococcus

Which antibiotic to start treatment?

Any third generation antibiotic which is sensitive to the microbiological flora and good penetration to ascitic fluid is good. Most studied antibiotic is cefotaxime- 2g BD for 5days is the BSG recommendation.

Other alternatives are ceftriaxone, ceftazidime or co-amoxiclav.

Oral treatment works?

Asymptomatic patients with good bowel sound can be treated with oral ciprofloxacin (750mg BD) or co-amoxiclav (1.2g TDS)

Is there any role of primary prophylaxis?

Some centres suggest primary prophylaxis when ascitic fluid protein is lower than 10gm/L but no consensus and currently no good evidence to suggest its use.

Discuss secondary prophylaxis?

After first episode of SBP approx 70% of the patients will have recurrence at the end of one year.

Should be given secondary prophylaxis with Norfloxacin 400mg OD or ciprofloxacin 500mg OD- reduces the probability of recurrence of SBP from 68% to 20%

Does it precipitate renal failure?

Development of renal failure occurs in 30% of patients of SBP and is one of the strongest predictors of mortality in SBP.

Is there any use of albumin in SBP?

BSG supports the recommendations of the Barcelona group of infusing albumin (1.5gm /Kg on Day 1 and 1gm/Kg on Day 3) in SBP in patients with high creatinine or rising creatinine but does not support routine use.

Is it indication for referral to transplant centre?

Yes.
Probability of survival at one year after an episode of SBP is 30-50% which falls to 25-30% at two years. So patients recovering form SBP should be referred to transplant centre for consideration of liver transplant, if clinically appropriate.

Ref

British Society of Gastroenterology guidelines for the management of ascites in cirrhosis

1. SBP is confirmed by positive bacterial culture of the ascitic fluid and ascitic fluid neutrophil count of >500cells/mm3 – False ( >250 neutrophils /mm3)
2. Occurs in the background of advanced cirrhosis, particularly when ascitic fluid protein goes below 20mg/L – FALSE (below 10mg/L)
3. Usual source is gut bacteria - TRUE
4. occurs in 5-10% of cirrhotic hospitalised patients – FALSE – 10-30%
5. Untreated mortality is 90% – TRUE
6. GI bleeding is a risk factor for SBP in cirrhotic pts - TRUE
7. The commonest symptom in SBP is confusion – FALSE (Fever> abdominal pain> confusion)
8. Gram stain a useful diagnostic test - FALSE
9. Neutrophil  count: normally in hundreds in SBP and in thousands in Secondary BP - TRUE
10. Sugar: >2.8 mmol/L in Secondary BP – FALSE ( Sugar is <2.8mmol/L as neutrophils consume sugar)
11. The microbiological flora is usually either E.Coli, Streptococcus or enterococcus – TRUE
12. Primary prophylaxis is often indicated when protein is lower than 10gm/L – FALSE
13. After first episode of SBP approx 70% of the patients will have recurrence at the end of one year. – TRUE
14. Development of renal failure occurs in 70% of patients of SBP – FALSE (in 30%)
15. Patients recovering from SBP should be referred to transplant centre – TRUE

Take home message:

Suspect SBP when—- ascites with cirrhosis

+ fever or
abdominal pain or
confusion or
abdominal tenderness or
diarrhoea or
renal failure

Ascitic tap-

1. Neutrophils>250cells/mm3 (send in EDTA tube not white top container)
2. Culture (send in blood culture bottle not white top container)
3. Protein <10g/L
4. Sugar – near normal

Exclude secondary bacterial peritonitis

1. Neutrophil  count: normally in hundreds in SBP and in thousands in Secondary BP
2. Sugar: <2.8 mmol/L in Secondary BP because high numbers of neutrophil consume sugar and in frank perforation sugar level can be zero
3. Protein: low (<10g/L) in SBP, higher in Secondary BP
4. LDH: High in secondary BP greater than the upper limit of normal for serum
5. Also Erect CXR shows gas under diaphragm/ gastrograffin enema shows extravasation of contrast into the peritoneum.

Start cefotaxime 2g bd x 5 days
Change later depending on sensitivities

Asymptomatic patients with good bowel sound can be treated with oral ciprofloxacin (750mg BD) or co-amoxiclav (1.2g TDS)

Prevention of ARF
BSG supports the recommendations of the Barcelona group of infusing albumin (1.5gm /Kg on Day 1 and 1gm/Kg on Day 3) in SBP in patients with high creatinine or rising creatinine but does not support routine use.

After an attack of SBP

1. Refer patient for consideration of transplant- Probability of survival at one year after an episode of SBP is 30-50%
2. Patient should be given secondary prophylaxis with Norfloxacin 400mg OD or ciprofloxacin 500mg OD- reduces the probability of recurrence of SBP from 68% to 20%

HRS is a potentially reversible syndrome that occurs in patients with cirrhosis, ascites and liver failure, as well as in patients with acute liver failure or alcoholic hepatitis. It is caused by intrarenal vasoconstriction which occurs in patients with end-stage liver disease and circulatory dysfunction. Circulatory dysfunction is characterized by vasodilatation in the splanchnic circulation with a relatively low and insufficient cardiac output, leading to effective hypovolaemia. HRS may occur spontaneously with worsening liver function, or secondary to a precipitating event such as bacterial infection or large volume paracentesis without albumin administration.

What are the types of HRS?

There are two types of HRS.

Type-1 HRS is characterized by rapid progressive renal failure defined by doubling of the initial serum creatinine concentrations to a level greater than 226 mmol/l in less than 2 weeks.

Type-2 HRS is characterized by moderate renal failure (serum creatinine from 133 to 226 mmol/l), with a steady or slowly progressive course. It appears spontaneously, but can also follow a precipitating event. Type-2 HRS is typically associated with refractory ascites. Survival of patients with type-2 HRS is shorter than that of non-azotaemic cirrhotic patients with ascites but better than that of patients with type-1 HRS.

HRS means type -1 HRS, unless otherwise indicated.

How do you diagnose HRS?

New diagnostic hepatorenal syndrome criteria in cirrhosis

1. Cirrhosis with ascites.
2. Serum creatinine >133 mmol/l (1.5 mg/dl).
3. No improvement of serum creatinine (decrease to a level of (133 mmol/l) after at least 2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day.
4. Absence of shock.
5. No current or recent treatment with nephrotoxic drugs.
6. Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhaematuria (>50 red blood cells per high power field) and/or abnormal renal USS.

How do you treat HRS?

Terlipressin- It should be started at 0.5– 1 mg every 4–6 h.

• If there is no early response (>25% decrease in creatinine levels after 2 days), the dose can be doubled every 2 days up to a max of 12 mg/day.
• Treatment can be stopped if serum creatinine does not decrease by at least 50% after 7 days of the highest dose, or if there is no reduction after the first 3 days.
• In patients with early response, treatment should be extended until reversal of HRS or for a maximum of 14 days.
• Terlipressin may induce ischaemic side effects and arrhythmias requiring drug discontinuation. Severe side effects of the treatment are uncommon (5-10%)

Albumin-
In the absence of dose/effect studies, the dose of albumin recommended is 1 g/kg of body weight on the first day, up to a maximum of 100 g, followed by 20–40 g/day. Albumin may be discontinued if serum albumin concentration is >45 g/l.

Complete response (reversal of HRS): defined as decrease of serum creatinine to below 133 mmol/l occurs in 60% with the above regimen.

No response: defined as no decrease of serum creatinine or decrease to less than 50% of its pre-treatment value, with a final level above 133 mmol/l (1.5 mg/dl).

What are the options if the patient relapses after treatment?

Renal failure may recur after discontinuation of therapy (relapse- occurs in 20%), but retreatment is usually effective. In contrast, partial response is frequently followed by a severe and irreversible relapse of renal failure.

Do all patients with HRS need a central line for treatment?

Albumin may cause pulmonary oedema and should be withdrawn if this happens. Since this complication is uncommon, catheterization to monitor central venous pressure is not mandatory, but careful physical and radiological monitoring of the cardiopulmonary function is recommended.

Is TIPS effective in non responders?

Patients with partial or no response to vasoconstrictors may be treated with TIPS. The small amount of data on the use of TIPS in HRS shows that it improves renal function and eliminates ascites. In patients with type-1 HRS, TIPS may also improve survival, but this is debatable in patients with type-2 HRS. The major disadvantage of TIPS is its low applicability. Indeed, it should not be used in patients with serum bilirubin levels more than 85.5 mmol/l (5 mg/dl), severe encephalopathy or history of recurrent encephalopathy, severe bacterial infection, and serious cardiac or pulmonary dysfunction or a Child–Pugh score more than 11.

What is the role of extracorporeal albumin dialysis (ECAD) in HRS treatment?

If there are contra-indications to TIPS, ECAD (could be used in the setting of prospective trials. ECAD decreases serum creatinine levels, but it is not definitively known whether or not this effect is due to a true improvement of renal function or simply to the filtration process.

What is the role of liver transplantation?

Liver transplantation is the treatment of choice for both type-1 and type-2 HRS. Morbidity after liver transplantation is higher in patients with HRS than in those without HRS, although the long-term probability of survival is only slightly lower. Patients with HRS who undergo liver transplantation tend to have more complications, spend more days in intensive care units and have higher in-hospital mortality rates than liver transplant patients without HRS. However, their 3-year probability of survival is acceptable (60% vs. 70–80% in liver transplant patients without HRS). The main limitation of liver transplantation is that due to the shortage of donor organs, and their extremely short survival, most patients with type-1 HRS die before transplantation.

Can HRS be prevented?

The incidence of HRS in patients with SBP may be reduced by albumin administration, prevention which was associated with improved survival. The suggested dose of albumin is 1.5 g/kg body weight on the first day and 1 g/kg body weight on the third day, up to a maximum of 150 and 100 g, respectively. As type-1 HRS almost exclusively occurred in patients with serum bilirubin >68 mmol/l (4 mg/dl) and serum creatinine >88.4 mmol/l (1 mg/dl), the prophylactic use of albumin could probably be restricted to these patients, but trials need to be conducted so that the optimum dosage to be used can be defined more precisely. So, Albumin administration is clearly indicated for patients with SBP and serum bilirubin levels more than 68.4 mmol/l or serum creatinine levels more than 88.4 mmol/l.

Is Terlipressin and albumin regime effective for type 2 HRS?

There are no definite data to support the use of vasoconstrictors in type 2 HRS patients. TIPS can be used to improve refractory ascites, which is often associated with type-2 HRS. Data on the effect of TIPS on survival are still insufficient.

A patient with cirrhosis and ascites admitted with pneumonia develops renal failure in the absence of septic shock? Is it HRS?

Renal failure in the setting of ongoing bacterial infection, but in the absence of septic shock, is now considered HRS. This means treatment of HRS can be started without waiting for complete recovery from the infection.

Ref

1. Salerno F et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310-1318.

Cirrhosis (75%), malignancy (10%), heart failure (3%), tuberculosis (2%), pancreatitis (1%), and other rare causes.

Discuss the diagnostic algorithm for ascites?

• History and physical examination frequently reveal the underlying cause of ascites.
• Diagnostic paracentesis- essential tests include cell count and type, ascitic fluid albumin or protein, ascitic fluid culture (in blood culture bottles) and ascitic fluid amylase. Ascitic fluid cytology should be requested when there is a clinical suspicion of underlying malignancy. Gram’s stain of ascitic fluid is not indicated, as it is rarely helpful.
• An ascitic neutrophil count of > =250 cells/mm3 is diagnostic of SBP in the absence of a known perforated viscus or inflammation of intrabdominal organs.
• High ascitic amylase is diagnostic of pancreatic ascites
• USS scan to evaluate for portal hypertension. CT scan may be needed if malignancy is suspected

Discuss serum albumin ascitic gradient (SAAG)?

SA-AG = serum albumin concentration minus ascitic fluid albumin concentration. Conventionally ascites is classified as exudate (ascitic fluid protein >25g/l) or transudate (<25g/l). The purpose of this subdivision is to help identify the cause of ascites. Thus ‘‘malignancy classically causes an exudative ascites and cirrhosis causes a transudate’’. However, there are many misconceptions in clinical practice. For example, it is often presumed that cardiac ascites is a transudate when this is rarely the case, ascitic protein is >25 g/l in up to 30% of patients with cirrhosis, and patients with cirrhosis and tuberculous ascites may have a low ascitic protein. The serum ascites-albumin gradient (SA-AG) is far
superior in categorising ascites with 97% accuracy. Thus
High SAAG (>=11g/l) is caused by cirrhosis, cardiac failure, nephrotic syndrome
Low SAAG (<11g/l) is caused by malignancy, pancreatitis, tuberculosis

Discuss the various grades of ascites?
Grade 1 (mild). Ascites is only detectable by ultrasound examination.
Grade 2 (moderate). Ascites causing moderate symmetrical distension of the abdomen.
Grade 3 (large). Ascites causing marked abdominal distension.
Initial investigations

Discuss the management of ascites in cirrhosis?
The development of ascites is an important landmark in the natural history of cirrhosis as it is associated with a 50% mortality over two years and signifies the need to consider liver transplantation as a therapeutic option.

• Bed rest is not recommended for the treatment of ascites.
• Dietary salt should be restricted to a no-added salt diet of 90 mmol salt/day (5.2 g salt/day).
• There is no role for water restriction in patients with uncomplicated ascites.
• Spironolactone is the drug of choice in the initial treatment of ascites due to cirrhosis. It is started at a daily dose 100 mg may and progressively increased up to 400 mg to achieve adequate natriuresis. It is a better diuretic than furosemide. The dose is increased every 3-5 days. Side effects- decreased libido, impotence, and gynaecomastia in men and menstrual irregularity in women and hyperkalaemia
• Furosemide is added if 400 mg/day of spironolactone fails to resolve ascites. The initial dose of furosemide is 40 mg/day and it is generally increased every 2–3 days up to a dose not exceeding 160 mg/day.
• Therapeutic paracentesis is the first line treatment for patients with large or uncomfortable ascites

Discuss the management of hyponatremia in cirrhotic ascites?

• Serum sodium 126–135 mmol/l and normal serum creatinine- Continue diuretic therapy but observe serum electrolytes. Do not water restrict.
• Serum sodium 121–125 mmol/l and normal serum creatinine- British society of Gastroenterology (BSG) recommends stopping diuretic therapy or adopting a more cautious approach.
• Serum sodium 121–125 mmol/l and serum creatinine elevated (>150 mmol/l or >120 mmol/l and rising) – Stop diuretics and give volume expansion.
• Serum sodium (<=120 mmol/l, stop diuretics. Management of these patients is difficult and controversial. We (BSG) believe that most patients should undergo volume expansion with colloid (haemacel, gelofusine, or voluven) or saline. However, avoid increasing serum sodium by >12 mmol/l per 24 hours.

Discuss hyponatremia and water restriction?
Water restriction for patients with ascites and hyponatraemia is the standard clinical practice. However, the best management of these patients is not known. However, hyponatremia is caused by non-osmotic secretion of ADH due to effective central hypovolemia in cirrhotic ascites. Thus water restriction may worsen the problem by exacerbating the hypovolemia (and further increases in ADH). Therefore, some hepatologists, advocate further plasma
expansion to normalise and inhibit stimulation of ADH release. Gelofusine, haemacel, and
4.5% albumin solutions contain sodium concentrations equivalent to normal saline (154 mmol/l). This will worsen their salt retention but it is better to have ascites with normal renal function than to develop potentially irreversible renal failure.
Water restriction should be reserved for those who are clinically euvolaemic with severe hyponatraemia in which free water clearance is decreased, and who are not currently taking diuretics, and in whom serum creatinine is normal.

What is the target weight loss in cirrhotic ascites?

In patients with severe oedema there is no need to slow down the rate of daily weight loss. Once the oedema has resolved but ascites persists, then the rate of weight loss should not exceed about 0.5 kg/day.

How do you assess compliance with salt restriction?

By measurement of urinary sodium excretion. If 24 hr urinary sodium exceeds the recommended sodium intake (90 mmol/day) – then the patient is non compliant

Discuss refractory ascites (RA)?

• Ascites that cannot be mobilised or early recurrence of which (that is, after therapeutic paracentesis) cannot be satisfactorily prevented by medical therapy. This includes two different subgroups.
  Diuretic resistant ascites—ascites that is refractory to dietary sodium restriction and intensive diuretic treatment (spironolactone 400 mg/day and furosemide 160 mg/day for at least one week, and a salt restricted diet of less than 90 mmol/day (5.2 g of salt)/day).
  Diuretic intractable ascites—ascites that is refractory to therapy due to the development of diuretic induced complications that preclude the use of an effective diuretic dosage.
• 50% of patients with refractory ascites die within six months.
• Therapeutic paracentesis is the first line treatment for patients with RA.
• TIPS can be used for the treatment of RA requiring frequent therapeutic paracentesis (> 3 a month) with appropriate assessment of risk benefit ratio.
• Liver transplantation, if appropriate, is the definitive treatment option.

Ref

1. EASL Clinical Practice Guidelines (2010): The management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis
2. AASLD Practice Guidelines (2009): Management of Adult Patients with Ascites Due to Cirrhosis: An Update
3. Moore KP and Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006; 55; 1-12 (archived copy at Webcite)