What’s new?

C In patients with hepatorenal syndrome (HRS), cardiac output is

inadequate to maintain normal blood pressure and this may be

secondary to cirrhotic cardiomyopathy

C The most common trigger for the development of type 1 HRS is

bacterial infection

C Renal function and survival in HRS can be improved by phar-

MANAGEMENT PROBLEMS IN LIVER DISEASE

Diagnosis and managementof ascites and hepatorenalsyndrome (acute kidneyinjury) in cirrhosisKevin Moore

macological therapy

AbstractThe development of ascites and/or the hepatorenal syndrome in liver

disease signifies the beginning of the end of liver function (decompensa-

tion). These patients need careful medical management to reverse these

abnormalities, and identify any precipitating cause such as sepsis or

complication such as spontaneous bacterial peritonitis. Once ascites

develops, all patients should be considered for liver transplantation

since the long-term prognosis is poor. Patients should start modest salt

restriction, and spironolactone as the first-line diuretic drug. Patients

with alcoholic liver disease need to stop drinking.

The development of hepatorenal syndrome is due to a combination of

vasodilatation causing a lowering of blood pressure, activation of the

sympathetic nervous system, impairment of cardiac function, and

increased synthesis of vasoactive mediators. Patients developing hepa-

torenal syndrome should be managed with volume expansion, terlipres-

sin, and a low threshold for intravenous antibiotics.

Keywords acute kidney injury in cirrhosis; AKI; hepatorenal syndrome;

paracentesis; renal failure in/and cirrhosis; spontaneous bacterial

peritonitis; transjugular intra-hepatic portosystemic shunt (TIPS)

Introduction and pathophysiology

Fifty percent (50%) of patients with compensated cirrhosis

develop ascites within 10 years of the onset of cirrhosis. Ascites

occurs only in patients with chronic liver disease and portal

hypertension. It results from sodium and water retention that

follows activation of arterial and cardiopulmonary volume

receptors, and homeostatic activation of the sympathetic nervous

system and the renineangiotensinealdosterone system,

secondary to arterial splanchnic vasodilatation and decreased

Kevin Moore BSc MB BS PhD FRCP is Professor of Hepatology at the UCL

Institute of Hepatology, Royal Free Campus, University College London

Medical School, UK. His interests include the role of oxidative stress

and vascular function in liver disease, with an emphasis on complica-

tions of portal hypertension. Clinically Professor Moore practises as

a Hepatologist, but is also accredited (on the specialist register) for

Clinical Pharmacology and Therapeutics and General Internal Medicine

(GIM). He is co-author of the Oxford Handbook of Acute Medicine.

Conflicts of interest: I have been an advisor to Servier, Norgine, Cum-

berland Pharmaceuticals.

MEDICINE 39:10 612

effective arterial blood volume (see Figure 1). Expansion of the

extracellular fluid in the presence of portal hypertension

enhances formation of hepatic lymph, extravasation of peritoneal

fluid and formation of ascites and oedema. The European Asso-

ciation for the Study of the Liver (EASL) has recently published

more extensive clinical guidelines than are presented here.1

The development of ascites is associated with a poor prognosis

in patients with cirrhosis, since these patients may develop spon-

taneous bacterial peritonitis (SBP) or the hepatorenal syndrome

(HRS), with an increased risk of variceal bleeding or sepsis.

The probability of survival at 2 and 5 years after the appear-

ance of ascites in patients with cirrhosis is estimated to be about

65%, and 35% respectively1 and the development of ascites has

a marked impact on quality of life. However, prognosis is

considerably better in patients with alcoholic cirrhosis if they

stop drinking alcohol. Low serum sodium concentration is the

most powerful predictor of mortality, and about 50% of patients

presenting with ascites have a serum sodium concentration less

than 135 mmol/litre.2 Thus, patients with ascites should always

be considered for referral for liver transplantation.

While the majority of cases (75%) of patients who present

with ascites have underlying cirrhosis and portal hypertension,

the remaining 25% have alternative causes (see Box 1).

Diagnosis of ascites

A full history, physical examination, abdominal ultrasound,

measurement of liver and renal function, and serum and urine

electrolytes, as well as an analysis of the ascitic fluid should be

undertaken in all patients. Patients should be asked about risk

factors for liver diseases, and a history of cancer, tuberculosis and

heart failure. The presence of jaundice, spider naevi, palmar

erythema, hepatomegaly and/or splenomegaly suggests under-

lying cirrhosis as a cause of ascites. An abdominal ultrasound is

needed to confirm the presence of ascites and a nodular looking

liver, and to screen for hepatocellular carcinoma (or other malig-

nancy) and portal vein thrombosis; it may even reveal dilated

hepatic veins that may suggest a cardiac cause, or thrombosis of

the hepatic veins (BuddeChiari syndrome). Portal vein throm-

bosis in the absence of cirrhosis does not cause ascites unless there

is a major insult such as gastrointestinal (GI) bleeding.

A diagnostic paracentesis with an appropriate ascitic fluid

analysis is essential in all patients investigated for ascites, before

any therapy, to rule out spontaneous bacterial peritonitis (SBP)

and look for other causes of ascites. When the diagnosis of

cirrhosis is not clinically evident, ascites due to portal hyper-

tension can be differentiated from ascites due to other causes by

� 2011 Published by Elsevier Ltd.

Compensatedcirrhosis

Sinusoidal portal hypertension

Splanchnic arteriolar vasodilation

Decreased effective arterial blood volume

High-pressure baroreceptor-mediatedstimulation of renin-angiotensin-aldosterone

and sympathetic nervous systemsand vasospressin

Sodium andwater retention

Adequate to normalizecirculatory homeostasis

Inadequate to normalizecirculatory homeostasis

Increase inplasma volume

Moderate Severe

Decompensatedcirrhosis

The development of portal hypertension leads to system vasodilatation of the splanchnic vascular bed, decreased effective arterial volume, leading to activation of

the sympathetic nervous system and renion-angiotensin system, and subsequently increased sodium and water retention.

Return of plasma renin, aldosterone, noradrenaline and vasopressin levels to

normal values

Plasma renin, aldosterone, noradrenaline and vasopressin

levels remain at high values

Continuous renal sodium and water retention

Ascites formation

Return of renal sodium and water excretion to normal

Pathogenesis of salt and water retention in cirrhosis

Figure 1 From Schrier RW et al3, with kind permission of John Wiley & Sons.

MANAGEMENT PROBLEMS IN LIVER DISEASE

means of the serum:ascites albumin gradient (SAAG). This is

calculated by subtracting the ascitic albumin concentration from

the serum albumin. An SAAG of 11 g/litre or more identifies

portal hypertension as the cause with 97% accuracy.

The ascitic fluid should be inoculated into a blood culture bottle

and a plain plastic tube or EDTA tube for examination by micros-

copy. An ascitic polymorphonuclear leucocyte count over 250/mm3

isdiagnostic of SBP, in the absenceof abdominal surgically treatable

sources of infection. Coulter counter counts of white blood cells

(WBCs) may be unreliable. Ascitic fluid amylase activity should be

measured. A clinical suspicion of alternative causes of ascites,

suggestedby lymphocytosis or SAAGunder 11 g/litre, justifiesother

Causes of ascites

C Cirrhosis and portal hypertension 75%

C Malignancy 10%

C Pancreatic ascites 2%

C Tuberculous ascites 2%

C Cardiac causes 3%

C Miscellaneous 8%

Box 1

MEDICINE 39:10 613

tests, such as cytology, polymerase chain reation (PCR) and culture

for mycobacteria.

Management of ascites

Mild or moderate ascites: patients with mild or moderate ascites

can generally be treated as outpatients. They should be advised

to reduce their sodium intake with a no-added-salt diet, and to

avoid foods with a high salt content (e.g. prepared meals).

Patients with moderate ascites will usually benefit from spi-

ronolactone to increase urinary sodium excretion. Loop diuretics

should be avoided unless ascites is difficult to treat.

Spironolactone dosage should start at 100 mg/day and be

increased (in 100 mg increments) every 7e10 days to

a maximum of 400 mg/day if there is no response (no loss of

ascites as assessed by weight, and no change in urine sodium

concentration, see below). In patients who do not respond to

aldosterone antagonists (<2 kg weight loss/week until clinical

resolution of ascites), or in patients who develop hyperkalemia,

furosemide should be added, starting at 40 mg/day and

increasing by 40-mg increments to a maximum of 160 mg/day.

Monitoring e during the first 4 weeks of diuretic therapy,

serum urea and electrolytes should be measured weekly. Patients

with avid sodium retention excrete virtually no sodium and may

benefit from a more rapid escalation of diuretic therapy with

weekly monitoring of renal function. Thus, measuring urinary

� 2011 Published by Elsevier Ltd.

Gut flora

Bacteria in lymphatic system

Bacteraemia

Bacterascites

Opsonins ↓↓ Opsonins ↓ Opsonins ↑

Bacteria in hepatic lymph

Pneumonia

Complement

UTI

Instrumentation

Pathophysiology of spontaneous bacterial peritonitis (SBP)

Drugs relatively contraindicated in ascites

C Non-steroidal anti-inflammatory drugs, including aspirin

C Gentamicin

C Amikacin

C a-blockers

C b-blockers

C Angiotensin-converting enzyme inhibitors

C Contrast media

C Dipyridamole

Box 2

MANAGEMENT PROBLEMS IN LIVER DISEASE

sodium on a spot urine sample during treatment is a useful test;

those with a relatively high urine sodium concentration (>40

mmol/litre) are more likely to respond to diuretic therapy.

Followingmobilization of ascites, the dose of diuretics should be

reduced to avoid diuretic-induced complications while preventing

clinically significant ascites. Alcohol abstinence is crucial for the

control of ascites in patients with alcohol-related cirrhosis and can

lead to withdrawal of diuretics. The use of diuretics in cirrhotic

patients with ascites may be associated with several complications,

such as renal failure, hepatic encephalopathy, electrolyte and acid-

base disorders, gynaecomastia and muscle cramps.

The commonest complications of spironolactone use are

gynaecomastia, hyponatraemia and hyperkalaemia. In the UK, it

is common practice to stop diuretics temporarily in patients

whose serum sodium decreases to less than 125 mmol/litre

(although EASL guidelines state 120 mmol/litre). If there is

a significant rise in serum creatinine, diuretics should be stopped

and rehydration initiated if necessary.

Severe ascites: large-volume paracentesis (LVP) combined with

the infusion of human albumin is the treatment of choice. It ismore

effective than diuretics and shortens the duration of hospitaliza-

tion, as well as the frequency of hyponatraemia, renal impairment

and hepatic encephalopathy. There is no limit to the amount of

ascites that can be removed in a single session, and it should be

completedwithin a single tapwith removal of the drainage cannula

within 6 hours of initiation. Within the first hour, there is a reduc-

tion of intra-abdominal pressure, an increase in cardiac output,

a modest reduction of right atrial pressure, a lowering of systemic

vascular resistance and a mild lowering of blood pressure.

Albumin (20%) is the most effective plasma expander to

prevent postparacentesis-related circulatory dysfunction. The

recommended amount of albumin to be infused during para-

centesis is 8 g for every litre tapped, and this should be given at

the conclusion of paracentesis rather than concurrently. If

fewer than 5 litres of ascites are removed, human albumin can be

safely replaced by an alternative plasma volume expander, such

as gelofusine (150 ml/litre of ascites removed). Spironolactone

(100 mg/day) should be started either before or following para-

centesis, if the patient is not already taking it.

Refractory ascites is defined as ‘ascites that cannot be mobilized

or the early recurrence of which (i.e. after LVP) cannot be satis-

factorily prevented by medical therapy’. Once ascites becomes

refractory to medical treatment, the median survival of patients is

about 6 months. Repeated LVP is an effective and safe therapy. A

recent study showed that patients with refractory ascites taking

b-blockers have a marked reduction in survival, so b-blockers

should be STOPPED in all patients with refractory ascites.

SBP CNNA Normal ascites

Drugs contraindicated in patients with ascites

Micro-organisms enter the blood stream and lymphatic system and

enter ascitic fluid through lymphatic drainage. If opsonic adctivity is

high, i.e the body is capable of eradicating the infection then infection

resolves. If the host defence is low (low ascitic total protein 15g/litre),

low complement or low ascitic immunoglobulins, then spontaneous

bacterial peritonitis develops.

CNNA; culture-negative neutrocytic ascites

Figure 2

Box 2 lists drugs that are contraindicated in patients with ascites.

Use of transjugular intra-hepatic portosystemic shunts (TIPS)

for ascites: insertion of a TIPS shunt decreases the portal pressure.

Within 4 weeks after TIPS insertion there is usually an improve-

ment of urinary sodium excretion and renal function. Complica-

tions include the development of hepatic encephalopathy, which

occurs in 30e50% of patients, shunt thrombosis and stenosis.

MEDICINE 39:10 614

Spontaneous bacterial peritonitis

SBP occurs in about 2% of outpatients and about 10% of patients

admitted to hospital with cirrhosis and ascites; it has an overall

mortality of about 20e30%. In half of all episodes of SBP, the

condition is present at the time of hospital admission (Figure 2).

In 50% of patients, SBP is asymptomatic. Symptoms include:

� abdominal pain

� abdominal tenderness

� vomiting

� 2011 Published by Elsevier Ltd.

Factors involved in the pathogenesis of hepatorenalsyndrome (HRS)

C Development of splanchnic vasodilatation, which causes

a reduction in effective arterial blood volume and a decrease

in mean arterial pressure

C Activation of the sympathetic nervous system and the

renineangiotensinealdosterone system, which causes renal

vasoconstriction and a shift in the renal autoregulatory curve,

making renal blood flow much more sensitive to changes in

mean arterial pressure

MANAGEMENT PROBLEMS IN LIVER DISEASE

� diarrhoea

� ileus

� signs of systemic inflammation, such as:

e hyper- or hypothermia

e chills

e altered WBC count

e tachycardia, and/or tachypnea

e worsening of liver function

e hepatic encephalopathy

e shock

e acute kidney injury

e gastrointestinal bleeding.

C Impaired cardiac function due to the development of cirrhotic

Management of SBP

cardiomyopathy. Although cardiac output is initially high in

patients with ascites, as cirrhosis advances cardiac function

becomes unable to compensate for the systemic vasodilata-

tion and blood pressure decreases

C Increased synthesis of several vasoactive mediators that may

affect renal blood flow or glomerular microcirculatory hae-

modynamics, such as cysteinyl leukotrienes, thromboxane A2,

F2-isoprostanes and endothelin-1, although the role of these

factors in the pathogenesis of HRS remains unknown

Box 3

1. Antibiotic therapy should be initiated immediately once the

diagnosis has beenmade, based on the ascitic neutrophil count

(>250/mm3). Intravenous cefotaxime (5 days) covers most

causative organisms and resolution of infection occurs in 80%.

Alternatively, amoxicillin/clavulanic acid or ciprofloxacin,

given intravenously for 48 hours, then orally, is also effective.

2. Intravenous albumin (20%) should be given at a dose of 1.5

g/kg body weight within 6 hours of diagnosis, followed by 1

g/kg on day 3. Albumin infusion decreases the incidence of

type 1 hepatorenal syndrome and mortality from 30% to

10%, compared with antibiotics alone.

Prophylaxis against SBP: prophylactic antibiotics (e.g. cipro-

floxacin 500 mg daily) should be given to all patients with a low

ascitic protein (<15 g/litre) or previous SBP (the recurrence rate

is w70%). All patients who present with GI bleeding and ascites

should undergo an ascitic tap since 25e65% have bacterial

infection at presentation.

Hyponatraemia

The development of hyponatraemia (<130 mmol/litre) is asso-

ciated with a poor prognosis. The most common cause of

hyponatraemia in cirrhosis is excess water retention. Occasional

patients present with salt depletion, and need to be treated with

sodium chloride. An infusion of sodium chloride 0.9% (sodium

concentration 154 mmol/litre) increases serum sodium slowly

(by no more than 8 mmol/litre sodium/day) and relatively

safely; hypertonic saline should be avoided.

Patients with water overload (hypervolaemic hyponatraemia)

are more difficult to treat. Fluid restriction is helpful in pre-

venting a further decrease in serum sodium, although it is rarely

effective in improving serum sodium concentration. However,

a new family of drugs, the vaptans, improve solute-free water

excretion by antagonizing selectively the effects of vasopressin

(AVP) in renal tubular V2 receptors and are effective in the

treatment of hyponatraemia in cirrhosis. These are not yet

licensed in the UK for use in cirrhosis, but have been licensed

for the management of inappropriate antidiuretic hormone

secretion.

Hepatorenal syndrome

Hepatorenal syndrome (HRS) is the occurrence of renal failure in

a patient with advanced liver disease in the absence of an iden-

tifiable cause. The prognosis remains poor, with a median

survival time of 1e3 months. The factors involved in the path-

ogenesis of HRS are shown in Box 3.

MEDICINE 39:10 615

Acute kidney injury in cirrhosis includes all causes of acute

deterioration of renal function, as indicated by an increase in serum

creatinine of more than 50% from baseline, or a rise in serum

creatinine of 26.4 mmol/litre in less than 48 hours. Chronic renal

disease is defined as an estimated glomerular filtration rate (eGFR)

of<60ml/minute, calculated using themodification of diet in renal

disease (MDRD6) formula, recognizing that this formula is not

perfect for cirrhoticpatients andwill include type2HRS(seebelow).

Traditionally, HRS is divided into two types. Type 1 HRS is

a rapidly progressive acute renal failure that develops concur-

rently with evidence of deterioration of liver function (e.g.

worsening coagulopathy and a significant elevation of serum

bilirubin). It commonly occurs in severe alcoholic hepatitis or in

patients with end-stage cirrhosis following a septic insult, such as

SBP, although in some patients it may occur in the absence of

any identifiable triggering event. Conventionally, type 1 HRS is

diagnosed only when serum creatinine increases by more than

100% from baseline to over 220 mmol/litre. Type 2 HRS occurs in

patients with refractory ascites and there is a steady but

moderate degree of functional renal failure, often with avid

sodium retention. In type 2 HRS, renal function fluctuates over

time; deterioration may be slow, or the patient may develop type

1 HRS following a precipitating event such as SBP.

In patients presenting with cirrhosis and ascites, the proba-

bility of developing HRS is 18% in the first year, and about 40%

at 5 years. Risk factors include hyponatraemia, arterial hypo-

tension, and elevated plasma renin activity or noradrenaline

concentration. However, recent studies have confirmed that the

development of sepsis is the most important risk factor. In

patients with cirrhosis and acute impairment of renal function

associated with bacterial infections, MELD score, neutrophil

count, and lack of resolution of infection are predictive factors of

the occurrence of renal failure. Moreover, the presence of

� 2011 Published by Elsevier Ltd.

MANAGEMENT PROBLEMS IN LIVER DISEASE

a systemic inflammatory response (SIRS) is an independent

predictive factor of mortality.

Management of hepatorenal syndrome: general measures

include careful monitoring of blood pressure and urine output,

daily liver and renal function tests, and assessment for the pres-

ence of bacterial infection (including ascitic, urine and blood

cultures), gastrointestinal bleeding and hepatic encephalopathy.

All patients should be given cautious volume expansion with

Hartmann’s solution or 4.5% human albumin solution (1e2

litres), assuming the patient has no signs of fluid overload, and

managed (ideally) in an intensive care or semi-intensive care unit.

Administration of terlipressin with intravenous 20% albumin

solution (1 g/kg on day 1, followed by 40 g/day thereafter)

improves renal function in patients with type 1 HRS. Treatment is

effective in about 35e40% of patients, and is associated with an

improved survival. Terlipressin should be started at a dose of 0.5

mg intravenously (IV) four times daily (2 mg/day) and the dose

increased if there is no reduction in serum creatinine, depending

on urine output and change in arterial pressure, up to a maximum

of 2 mg IV four times daily. Recent studies have suggested that

continuous intravenous infusion of terlipressin (suggested

regimen 3mg/day) ismore effective and has fewer adverse effects.

Terlipressin has less than 3% of the antidiuretic activity of vaso-

pressin, and a half-life of 24minutes, so a continuous infusion will

lead to steady state concentrations within 2 hours.

Adverse effects of terlipressin: cardiovascular or ischaemic

complications occur in 9e22% of patients treated with bolus

MEDICINE 39:10 616

injections of terlipressin, although most studies have excluded

patients with known ischaemic heart disease.

Both haemodialysis or continuous venovenous haemofiltra-

tion have been used to treat patients with type 1 HRS. In

general, renal replacement therapy should be considered in all

patients presenting with type 1 HRS, and those in whom HRS is

potentially reversible. The survival of patients with HRS with

renal support is around 15e20%. Patients with other evidence

of organ failure, such as respiratory failure, have a worse

prognosis.

Liver transplantation is the treatment of choice for both type 1

and type 2 HRS, with survival rates of approximately 65% in type

1 HRS. However, with current waiting times for liver trans-

plantation, it is not readily available in the UK. A

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2 Angeli P, Wong F, Watson H, Gin�es P. CAPPS Investigators. Hyponatremia

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1535e42.

3 Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rod�es J.

Peripheral arterial vasodilation hypothesis: a proposal for the initiation

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1151e7.

� 2011 Published by Elsevier Ltd.