Hepatorenal Syndrome

2009-03-06T20:03:00.000-08:00

MIDODRINE

Orthostatic Hypotension

Midodrine hydrochloride is used in the management of symptomatic orthostatic hypotension; the drug is designated an orphan drug by the US Food and Drug Administration (FDA) for such use. Midodrine should be used only after nondrug therapies (e.g., support hose, increased sodium intake, life-style modifications) and fluid expansion have failed. Clinical studies indicate that midodrine is more effective than placebo and at least as effective as ephedrine, fludrocortisone, or dihydroergotamine in the management of orthostatic hypotension. However, despite comparable increases in blood pressure, midodrine may be more effective than comparative drugs (e.g., ephedrine) in managing postural symptoms.Midodrine increases supine, sitting, and standing diastolic and systolic blood pressures, and may attenuate postural symptoms (e.g., dizziness, lightheadedness, syncope, impaired ability to stand). In several clinical studies, midodrine decreased supine and standing pulse rates in patients with orthostatic hypotension; however, the manufacturer states that clinically important changes in pulse rates generally do not occur in patients with impaired autonomic function receiving the drug. There is some evidence that efficacy of midodrine is related to autonomic function; patients with less severe autonomic dysfunction may benefit from midodrine therapy to a greater extent than those with severe autonomic dysfunction.The most potentially serious adverse effect of midodrine is supine hypertension (systolic blood pressure of 180 mm Hg or higher), reported in up to 25% of patients receiving the usual dosage (10 mg 3 times daily)of midodrine hydrochloride and in up to 50% of patients receiving 20-mg dosesof the drug in clinical studies. Patients should be advised to report promptly to their clinician symptoms of supine hypertension (e.g., cardiac awareness, pounding in the ears, headache, blurred vision). If supine hypertension occurs, the dosage of midodrine may be reduced;withdrawal of the drug may be necessary, particularly if supine hypertension persists. Sleeping with the head of the bed elevated may relieve supine hypertension in some patients.Concomitant use of midodrine and some vasoconstricting agents (e.g., phenylephrine, ephedrine, dihydroergotamine, phenylpropanolamine, pseudoephedrine) may cause an exaggerated hypertensive response. Patients receiving midodrine concomitantly with a vasoconstricting agent should be observed for possible additive hypertensive effects.Although midodrine used concomitantly with fludrocortisone (with or without sodium supplementation) appears to be well tolerated, patients should be monitored closely for supine hypertension during combination therapy.In addition, caution should be exercised in patients with ocular conditions when midodrine is used concomitantly with fludrocortisone (which can increase intraocular pressure and precipitate or aggravate glaucoma).Concomitant use of midodrine and agents that can cause bradycardia (e.g., cardiac glycosides, β-adrenergic blocking agents) may cause an exaggerated bradycardic response.Patients receiving midodrine concomitantly with such agents should be observed for possible additive bradycardic effects.The manufacturer states that midodrine also should be used with caution in patients with diabetes mellitus and in patients with a history of urinary retention.

Dosage and Administration

Administration

Midodrine hydrochloride is administered orally, usually in 3 equally divided doses daily. Since food does not appear to affect GI absorption of midodrine hydrochloride, the drug generally can be administered without regard to meals.

Dosage

Safety and efficacy of midodrine hydrochloride in children younger than 18 years of age have not been established. The manufacturer states that midodrine hydrochloride dosage adjustment based solely on age is not necessary in geriatric patients. Dosage adjustment based solely on gender also is not necessary.

Dosage in Renal and Hepatic Impairment

The manufacturer recommends that renal function be assessed prior to initiating midodrine therapy.Because the drug’s active metabolite (desglymidodrine) is eliminated by renal excretion and because safety and efficacy have not been studied systematically in patients with renal impairment to date, the manufacturer states that midodrine should be dosed cautiously in patients with abnormal renal function.The manufacturer recommends that midodrine hydrochloride therapy be initiated with 2.5-mg doses in such adults. Desglymidodrine is dialyzable.Midodrine has not been studied systematically in patients with hepatic impairment, and the effect of alterations in hepatic function on the disposition of the drug currently is not known.Therefore, while the manufacturer currently makes no specific recommendations for dosage adjustment in patients with hepatic impairment, midodrine should be used with caution in such patients.

Description

Midodrine is a synthetic sympathomimetic amine that is structurally similar to methoxamine. Midodrine is a prodrug and has little pharmacologic activity until metabolized to desglymidodrine .Desglymidodrine is a relatively long-acting α1-selective adrenergic agonistthat acts almost exclusively by a direct effect on peripheral α-adrenergic receptors of the arterial and venous vasculature, increasing vascular tone.Total peripheral resistance is increased,resulting in increased systolic and diastolic blood pressure. Standing blood pressure is increased by about 10–30 mm Hg 1 hour after a 10-mg dose of midodrine hydrochloride in patients with orthostatic hypotension, with some effect persisting for 2–3 hours;a 10-mg dose of the drug produces only modest elevations in supine and standing blood pressure in healthy individuals. Some evidence suggests that midodrine’s efficacy in improving standing blood pressure also may result in part from increased body weight during therapy with the drug, presumably secondary to expansion of extracellular fluid volume.Unlike most vasopressors, midodrine has virtually no stimulant effect on β-adrenergic receptors, including those of the heart. In addition, because desglymidodrine crosses the blood-brain barrier poorly, the drug generally does not appear to produce appreciable CNS stimulation. Because midodrine stimulates the trigone and sphincter of the urinary bladder, symptoms of urinary urgency can occur.The drug also stimulates pilomotor muscles, resulting in pilomotor effects (e.g., goose bumps, sensation of hair standing on end),and contracts the radial muscle of the iris, resulting in pupillary dilation. For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.

Adverse Effects List from First Databank

More Frequent

BURNING,ITCHING,PRICKLING OF SCALP, CHILLS, HYPERTENSION (severe), SUPINE HYPERTENSION (severe), URINARY FREQUENCY, URINARY RETENTION

Less Frequent

ANXIETY ,CONFUSION ,DRY MOUTH ,FACIAL FLUSHING ,,HEADACHE NERVOUSNESS ,SKIN RASH ,VASODILATION ,

Rare or Very Rare

BACKACHE ,BRADYCARDIA severe ,CANKER SORE ,DIZZINESS ,DROWSINESS ,DRY SKIN, FLATULENCE ,GASTROINTESTINAL DISTRESS ,HEARTBURN ,INSOMNIA ,LEG CRAMPS ,NAUSEA ,VISUAL FIELD DEFECT ,WEAKNESS

Drug Disease Contraindications from First DataBank

• Urinary Retention
• Acute Renal Disease
• Congestive Heart Failure
• Angina Pectoris
• Severe Uncontrolled Hypertension
• Thyrotoxicosis
• Pheochromocytoma
Lactation Precautions

PRECAUTION

• NO DATA AVAILABLE.
• EFFECT ON THE INFANT IS UNKNOWN

Pregnancy Precautions

ANIMAL STUDIES HAVE SHOWN ADVERSE EFFECT ON FETUS BUT NO WELL-CONTROLLED STUDIES IN HUMANS: POTENTIAL BENEFITS MAY WARRANT USE IN PREGNANT WOMEN DESPITE POTENTIAL RISKS; OR NO ANIMAL REPRODUCTION STUDIES AND NO ADEQUATE AND WELL-CONTROLLED STUDIES IN HUMANS.

Preparations

Midodrine Hydrochlorider
Oral
ProAmatine® (scored),Tablets
2.5 mg, 5 mg

Complications of Transjugular Intrahepatic Portosystemic Shunt

2008-07-31T07:11:00.000-07:00

Complications of Transjugular Intrahepatic Portosystemic Shunt

Procedural complications are generally seen in 10% or fewer patients after TIPS.Severe life-threatening bleeding has been reported in 1% to 2% of cases because of either puncture of the liver capsule with resulting hemoperitoneum or inadvertent puncture of the biliary tree with resulting hemobilia. Other major complications include contrast medium induced renal failure, heart failure, stent migration, fever, infection, transient arrhythmias, and inadvertent puncture of the gallbladder or other organs adjacent to the liver. Hemolysis, which is typically self-limited and mild, is not uncommon after TIPS.
Although procedural complications are relatively infrequent, hepatic encephalopathy is a common complication after TIPS, with a frequency in the range of 20% to 30%. This figure is not unexpected: TIPS represents a side-to-side portosystemic shunt that often results in complete diversion of portal flow, as well as a proportion of hepatic arterial blood flow, into the shunt (hepatofugal flow).

Related to post-TIPS encephalopathy, but much more ominous, is the development of accelerated liver failure after TIPS as a result of a critical loss of hepatic perfusion. A retrospective study at the University of California, San Francisco, noted clinically significant increases in serum bilirubin or alanine aminotransferase levels or prolongation of the prothrombin time in over one fourth of patients after TIPS.This deterioration in liver function is typically transient, but in a minority (about 5%) of patients progressive liver failure develops leading to expedited liver transplantation or death. Determining the natural history of liver function after TIPS will be an important challenge in the years to come and will be important for the understanding of the long-term utility of TIPS as well as for optimal patient selection.

The 30-day mortality rate after TIPS varies from 3% to 44% but is typically in the range of 10% to 15%.Appropriate patient selection is the key to reducing the mortality rate after TIPS. Death after TIPS is usually related to decompensated hepatic function and is caused by liver failure, infection, renal insufficiency, or multisystem organ failure. The paradox is that patients in whom TIPS is most clearly indicated for refractory bleeding or ascites often have advanced liver disease and are at greatest risk of dying after the procedure. Identification of specific prognostic factors that will help identify patients at greatest risk of death after TIPS has therefore been undertaken in a number of studies. Independent prognostic variables identified in these studies have been used to formulate models and nomograms that can be used to calculate risk scores and the probability of short-term mortality after TIPS.Although this approach is clearly valuable, none of the predictive models published to date has been validated independently and prospectively. They are best used currently to complement clinical judgment and to counsel patients and their families accordingly. Another major problem that has limited the utility of TIPS is occlusion or stenosis of the shunt. Narrowing or occlusion of TIPS stents may occur as an early event secondary to thrombosis or more chronically over a period of weeks or months as a result of pseudointimal hyperplasia. The latter occurrence is the much more common cause of significant shunt insufficiency after TIPS. From 30% to 50% of cases of shunt insufficiency present with recurrent variceal hemorrhage or ascites; the remainder are discovered during routine monitoring, a practice necessitated by the high frequency of shunt dysfunction.The actuarial frequency of shunt insufficiency ranges from 30% to 50% at 12 months and 47% to 68% at 24 months.[The higher frequencies of shunt insufficiency reported by some centers reflect, in part, a more aggressive approach to monitoring of TIPS patency with frequent venography, as well as classification of any narrowing as an abnormality. A more conservative and practical approach is to monitor shunt patency every 3 to 4 months by Doppler ultrasound, with venography performed when a suggestive ultrasonographic abnormality is found.Such abnormalities include a reduction in mean peak flow velocity in the TIPS below 0.5 m/second, reversal of previous hepatofugal flow to hepatopetal flow, and reversal of flow in the stented hepatic vein. Useful venographic criteria for shunt insufficiency include narrowing of the lumen by 75% or more or a pressure gradient across the shunt of 15 mm Hg or higher.

The development of strategies to prevent shunt stenosis is the focus of active research. Potential strategies include pharmacologic approaches to reduce shunt intimal hyperplasia, the primary cause of stenosis, and engineering and testing of stents covered by selectively permeable materials like polytetrafluoroethylene.

Indications n Contraindiations of TIPS

2008-07-31T07:05:00.000-07:00

Indications

Accepted indications
Control of refractory acute variceal bleeding
Prevention of refractory recurrent variceal bleeding in Child class B and C patients
Refractory hepatic hydrothorax
Budd-Chiari syndrome
Refractory ascites

Promising but unproven
Hepatorenal syndrome
Veno-occlusive disease

Unproven
Prevention of refractory variceal bleeding in Child class A patients
Initial therapy of acute variceal hemorrhage
Initial therapy to prevent recurrent variceal hemorrhage
Prevention of initial variceal hemorrhage
Reduction in intraoperative morbidity rate during liver transplantation
Hepatopulmonary syndrome

Contraindications

Absolute contraindications
Right-sided heart failure
Primary pulmonary hypertension
Polycystic liver disease
Severe hepatic failure
Portal vein thrombosis with cavernous transformation

Relative contraindications
Biliary obstruction
Active intrahepatic or systemic infection
Severe hepatic encephalopathy poorly controlled by medical therapy
Portal vein thrombosis without cavernous transformation

Transjugular Intrahepatic Portosystemic Shunt

2008-07-31T06:57:00.000-07:00

Transjugular Intrahepatic Portosystemic Shunt

Attempts to devise a less invasive approach to portal decompression led to the development of a nonsurgical shunt, the TIPS. The potential advantages of this technique include avoidance of general anesthesia, decreased procedural morbidity and mortality rates, and avoidance of surgery in the region of the hepatic hilum, which may be important in potential liver transplantation candidates.

A percutaneous method of creating a portosystemic shunt was first conceived in the late 1960s. Although technically successful, the shunts were short-lived, and all thrombosed within a few days. The development of expandable, implantable metallic stents provided a means, albeit imperfect, for maintaining shunt patency and allowed the widespread clinical implementation of this technique. The use of the flexible Wallstent endoprosthesis (Schneider, Minneapolis, MN) and several technical modifications have reduced procedure times to the range of 1 to 3 hours.Although a TIPS can be created successfully in over 95% of patients, considerable operator skill and experience in vascular and hepatobiliary interventional procedures are required.

There are minor variations in the technique among centers, and a variety of stents are in use. In brief, the technique employed at the University of California, San Francisco, is as follows: with the patient under sedation and analgesia, the right internal jugular vein is punctured percutaneously, and a vascular sheath is advanced into the inferior vena cava and then into a hepatic vein. Next, a Colapinto transjugular needle is advanced through the sheath caudally and anteriorly into the liver parenchyma. Portal vein puncture is detected by aspiration of blood and confirmed by injection of contrast medium. The portal pressure is measured after a branch of the portal venous system is entered. Subsequently, a guidewire is introduced and manipulated into the main portal vein. The needle is removed, an angioplasty balloon catheter is advanced over the guidewire, and the tract between the hepatic and portal veins is dilated. An 8- or 10-mm-diameter expandable metallic Wallstent is then deployed across the tract, with care taken to prevent intrusion of the stent into the portal vein or inferior vena cava in a manner that might compromise subsequent liver transplantation surgery. Portal venography is then repeated, and postshunt portal and vena caval pressures are determined.

Ideally, the portal vein inferior vena cava gradient is decreased to less than 12 mm Hg, the threshold below which varices rarely bleed. However, achieving this hemodynamic goal is not always possible with the relatively small stents used in the TIPS procedure. Typically, portal decompression is judged adequate if the gradient falls to 15 mm Hg or lower and varices can no longer be demonstrated radio graphically after injection of contrast medium into the splenic vein. When the gradient remains greater than 15 mm Hg or variceal flow persists, the stent is expanded to 10 or 12 mm in diameter, and, if necessary, a second parallel shunt is placed and the varices embolized with coils or alcohol. Patients are then monitored closely for bleeding for 12 to 24 hours. A Doppler ultrasonographic examination is performed the day after TIPS to assess patency of the shunt.

TIPS should not be performed in patients who have polycystic liver disease or cholangiohepatitis with intrahepatic bile duct dilation because of the high risk of traversing a cyst or bile duct, respectively. Like all portosystemic shunts, TIPS acutely increases right-sided cardiac pressure and therefore should not be performed in patients who have right-sided heart failure or primary pulmonary hypertension. Relative contraindications to TIPS include biliary obstruction, active intrahepatic or systemic infection, severe hepatic encephalopathy, and portal vein thrombosis.

2008-07-31T06:32:00.000-07:00

Overview of the Principles and Techniques of the Major Treatment Modalities

Endoscopic Therapy

Endoscopy is the cornerstone of the management of gastrointestinal hemorrhage both as a diagnostic and as a therapeutic modality. Once esophageal varices are identified as the source or likely source of bleeding, endoscopic options for treatment include injection sclerotherapy and variceal band ligation. Although these techniques do not treat the underlying portal hypertension, they have been shown to be effective in controlling variceal hemorrhage. The rates of success and complications of these endoscopic techniques depend in part on the experience of the operator and the technique employed.

Endoscopic Sclerotherapy

A variety of techniques have been employed in performing endoscopic sclerotherapy (EST) with the goal of arresting acute bleeding and preventing recurrent bleeding through the obliteration of varices by repeated injections. Injections may be directed into the veins (intravariceal injection) or into the esophageal wall adjacent to the variceal channels (paravariceal injection). Both techniques are effective, but intravariceal injection is more widely employed.Additionally, several different sclerosants are available, including 5% sodium morrhuate, 1% to 3% sodium tetradecyl sulfate (used in the United States), 5% ethanolamine oleate, 0.5% to 1% polidocanol (used in Europe), and absolute alcohol. Adhesives such as N-butyl-2- cyanoacrylate (tissue glue) have been used successfully. An optimal sclerosant for EST has not emerged; however, there are potentially important differences among these agents. For example, 1.5% sodium tetradecyl sulfate may be associated with more local ulceration and stricturing than polidocanol or ethanolamine oleate. The optimal volume of sclerosant to inject during a single session of EST is controversial. Typically 1 to 2 ml of sclerosant is used per injection and total volumes in the range of 10 to 15 ml seem to be optimal with regard to efficacy and safety.

The appropriate interval for performing follow-up EST after control of the initial hemorrhage also remains somewhat arbitrary. After the initial injection to control bleeding, a follow-up session 2 to 3 days later is common practice, usually followed by weekly or biweekly procedures until variceal obliteration is achieved. Thereafter, surveillance for reappearance of varices is usually conducted at intervals that extend from 1 month to 3 months and then 6 months. However, EST may be performed according to a variety of schedules, depending on patient tolerance, response to EST, and the development of sclerotherapy ulcers or other complications.

Endoscopic Variceal Ligation

The relatively high frequency of complications after EST (discussed later) led to the development of an alternative endoscopic therapy, endoscopic variceal ligation (EVL), also referred to as variceal banding.This technique was developed on the basis of principles established for the banding of hemorrhoids and involves the placement of elastic O ring ligatures on the varices, thereby causing strangulation of the veins . The original EVL device allowed only one band placement at a time, and the endoscope had to be removed to reload a new band after each ligation. Consequently, a plastic over tube was required to facilitate repeated esophageal intubation. Newer multiple-band devices have now replaced the original single-band device, thereby allowing the deployment of 6 to 10 rubber bands with a single esophageal intubation. Despite the improved technology, the use of EVL in the actively bleeding patient is still challenging because the plastic cylinder that carries the bands at the tip of the endoscope limits the operators field of vision. EVL is typically begun at the level of the gastroesophageal junction with additional bands deployed proximally. An endoscopic technique for EVL reported in 1999 that preserves the operators field of vision and employs detachable snares awaits further evaluation.

2008-07-12T10:37:00.000-07:00

Indications for liver biopsy

Percutaneous liver biopsy has a small but
inherent risk even in the most experienced
hands, and it should therefore only be performed
when the benefits of knowing the
histology outweigh the risks to the patient (in
terms of altering treatment or defining disease
outcome). These benefits should be continually
re-evaluated as new treatment options
become available such as has occurred with the
new antiviral therapies in viral hepatitis and in
liver transplantation.

Acute hepatitis of unknown etiology, including
possible drug related hepatitis, has long
been an indication for per cutaneous liver
biopsy, but liver biopsy in typical acute viral
hepatitis is usually not necessary. The usefulness
of liver biopsy in chronic viral hepatitis
was once hotly debated; however, with the
advent of new antiviral therapies there is no
doubt of the value of histology in assessing
those patients who will benefit from treatment
and assessing their response to it.
Patients with chronic hepatitis C virus infection
as determined by a positive serum
polymerase chain reaction test, who are being
considered for antiviral therapy should undergo
liver biopsy. Liver biopsy should probably
be undertaken even if the patient has normal
aminotransferases as it has been reported
that up to 50% of patients with active disease
have a normal serum alanine aminotransferase.

A liver biopsy sample is useful in
this instance in allowing an assessment of the
Hepatitis Activity Index (a necroinflammatory/
fibrosis scoring system) and to identify
confounding factors such as alcoholic liver disease
and haemochromatosis. Unfortunately,
histology of a single liver biopsy sample and the
monitoring of aminotransferases are poor predictors
of disease progression. Consequently,
repeat samples taken every two or three years
may be needed to assess disease progression
and prognosis.

In patients with raised serum ferritin or
where disorders of copper metabolism are suspected,
liver biopsy provides material for
measurement of iron and copper within the
liver parenchyma, although genetic analysis
may help to differentiate genetic haemochromatosis
from other causes of iron overload.
Culture of biopsy material can help in the
diagnosis of infections such as tuberculosis.
The need for liver biopsy in patients with
intrahepatic cholestasis from primary biliary
cirrhosis (PBC) and primary sclerosing
cholangitis (PSC) is more controversial.On the
one hand, the discovery that a persistentlyraised E2-antimitochondrial antibody (AMA)
confirms a diagnosis of PBC (even if patients
have no other signs or symptoms of PBC)
means that a liver biopsy in the early stages of
typical PBC (i.e., a middle aged woman with
cholestasis) may be unnecessary.On the
other, for more advanced disease liver biopsy
may be useful in accurately staging the disease.

The diagnosis of PSC related cholestasis is
usually made at endoscopic retrograde cholangiopancreatography
(ERCP) or MRI cholangiography,
and diagnostic histological features in
needle biopsy specimens are often not seen.
Liver biopsy is often useful in the diagnosis
and management of patients with alcohol
related liver diseases, as well as helping in the
diagnosis of infections such as tuberculosis.
Liver biopsy still remains part of the investigation
of pyrexia of unknown origin and is also
useful in the diagnosis of storage disorders.
Liver biopsy is often used in the investigation
of abnormal liver enzymes but this must be
taken in context, tempered by the results of
other routine investigations, and take into
account the patient’s details. For example, the
investigation of an isolated raised alkaline
phosphatase will be very different in an 80 year
old compared with a 25 year old. Raised
ã-glutamyl transpeptidase (GGT) activities
have been shown to be a sensitive marker of
alcohol misuse; however, an isolated increase in
GGT is not associated with major liver pathology
and is therefore not an adequate indication
on its own for liver biopsy.

The role of percutaneous liver biopsy in the
diagnosis of focal liver lesions depends largely
upon the clinical picture. In most patients with
malignant hepatocellular carcinoma ultrasound
scanning, CT, and measurement of
serum á-fetoprotein will allow a diagnosis to be
made (in the context of a space-occupying
lesion in a cirrhotic patient). Similarly, a patient
with a history of colonic resection for neoplasia
who presents with a solitary lesion in the liver
associated with raised serum carcinoembryonic
antigen, may not require a biopsy of the lesion
to make the diagnosis of a potentially resectable
metastasis. Liver biopsy also carries a
documented risk of seeding tumors down the
biopsy track.The magnitude of this risk is
currently unknown. Modern imaging techniques
can also help to define other types of
focal hepatic lesions such as haemangiomata
and focal nodular hyperplasia. In these situations,
some experts believe that the risk of
bleeding after biopsy of a malignant tumour is
greatest when the tumour is superficial and so
recommend traversing normal liver before
sampling tumour tissue. Fine needle aspiration
biopsy may be a safer option if material for histological
examination is required in the case of
a suspected angioma.

The use of liver biopsy after liver transplantation
is increasing, and policies on histological
monitoring vary between liver transplant units.
Some units perform routine biopsies on day 7
after transplant to assess acute rejection,
whereas others do annual review biopsies at
which abnormalities are frequently seen.
Liver biopsy is also useful in the diagnosis ofinvasive cytomegalovirus infection and in
assessing recurrent disease.
Using liver biopsy in the context of research
is controversial but has undoubtedly given
invaluable information in the past in such areas
as hepatitis C disease progression and the
development of new drugs.

We feel that these
biopsies should be performed in the context of
a clinical trial and where approval has been
given by the local research ethics committee. In
circumstances where the patient will derive no
potential benefit from the procedure, and will
thus only accrue the risks of that procedure, the
patient should be fully aware of this and give
written consent.

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2008-06-27T02:46:00.000-07:00

Transjugular intrahepatic portosystemic shunts

Only a few studies have reported on the effects of
transjugular intrahepatic portosystemic shunts (TIPS) in
patients with type 1 HRS. This procedure consists of
insertion of an intrahepatic stent between the portal and
hepatic veins by a transjugular approach. The main effect
is to lower portal pressure.
In type 1 HRS, TIPS improve
circulatory function and reduce the activity of
vasoconstrictor system.These effects are associated
with a slow, moderate to strong increase in renal perfusion
and GFR and a fall in serum creatinine concentrations in
about 60% of patients. Median survival after TIPS in
type 1 HRS is between 2 months and 4 months.As
with vasoconstrictor drugs, the improved renal function
probably, but not definitely, results in longer survival.
Information currently available on the use of TIPS in type
1 HRS has been obtained in a very selected population of
patients and may not be applicable to the whole
population of such patients. In fact, TIPS are thought to
be contraindicated in patients with severe liver failure
(high serum bilirubin concentrations and/or Child-Pugh
score greater than 12) or severe hepatic encephalopathy
because of the risk of inducing irreversible liver failure or
chronic disabling hepatic encephalopathy. No studies
have been reported that compared TIPS and
vasoconstrictors in type 1 HRS. Until comparative studies
are undertaken, vasoconstrictors appear to be the
treatment of choice in type 1 HRS because of apparently
similar efficacy, wider availability, and lower costs than
TIPS.

Liver Tranplantation in hepatorenal syndrome

2008-06-27T02:43:00.000-07:00

Liver transplantation

The treatment of choice for patients with cirrhosis and
type 1 HRS who are suitable for the procedure is liver
transplantation, because it allows both the liver disease
and the associated renal failure to be cured. The most
common contraindications for transplantation in HRS are
advanced age, active alcoholism, and infection. The main
problem in the use of liver transplantation for type 1 HRS
is that many patients die before transplantation is possible
because of the short survival expectancy and long waiting
times in most transplant centres. The issue can be solved
by assigning these patients a high priority for
transplantation from a cadaveric donor. This approach
was used with the former method of organ allocation used
by the United Network for Organ Sharing in the USA,
which classified patients with HRS in the 2a status, with a
median waiting time of about 7 days. Now this system
has been changed and livers are allocated on the basis of
the MELD (model of end-stage liver disease) score, which
is obtained by a formula including serum bilirubin, serum
creatinine, and international normalised ratio.Patients
with HRS have high MELD scores even when liver
function is preserved. This system was implemented in
the USA in early 2002, and the initial results of its use
have been reported recently.The policies for allocation
of livers from cadaveric donors are not uniform in other
countries. Whatever the system used for organ allocation,
HRS should probably be treated before transplantation is
done in an attempt to improve renal function. This step
may help reduce the (moderately) higher morbidity and
mortality after transplantation reported in patients with
HRS than in those without HRS. In fact, the outcome
of transplantation for patients with HRS treated with
vasoconstrictors (vasopressin analogues) before the
procedure does not differ from that of patients without
HRS.Combined liver and kidney transplantation for
patients with HRS does not improve the overall results
obtained with liver transplantation alone and should not
be used.

2008-06-14T02:52:00.000-07:00

Hepatorenal syndrome

The hepatorenal syndrome refers to renal failure of unknown etiology that occurs in a fully hydrated patient with severe, often progressive, liver disease. Urine biochemistry is characteristic and renal histopathology unremarkable.

The pathogenesis of the hepatorenal syndrome appears to involve intense intrarenal vasoconstriction and alteration in renal cortical blood flow, possibly due to an imbalance of prostaglandins and thromboxane. Early clinical experience suggested that only orthotopic liver transplantation was able to reverse the hepatorenal syndrome, although more recent evidence has reported up to 50 per cent survival in hepatorenal failure following paracetamol (acetaminophen) overdose. Renal failure is reversed after liver transplantation, suggesting that it is due to circulating or systemic factors. Excessive use of diuretics, sepsis, abdominal paracentesis, and gastrointestinal hemorrhage are all associated with an increased risk of the hepatorenal syndrome and suggest a functional etiology.

Clinical presentation

Typically, patients who develop the hepatorenal syndrome have signs of advanced liver disease, such as icterus, ascites, palmar erythema, spider angiomas, and hepatic encephalopathy. Laboratory findings confirm hepatic failure, with elevated serum bilirubin, liver enzymes, and ammonia. The impaired synthetic function of the liver usually results in hypoalbuminaemia and prolongation of the prothrombin time. Hyponatraemia, hypokalaemia, and alkalosis are common accompaniments. Hyponatraemia results from proximal tubular reabsorption of sodium and water with non-osmotic release of vasopressin. The first sign of hepatorenal syndrome is usually oliguria. The major differential diagnoses include prerenal azotaemia and vasomotor nephropathy (acute tubular necrosis). The patient with hepatorenal syndrome appears well hydrated and volume depletion can usually be excluded.

The FENa is less than 1 per cent and the urinary sodium less than 10 to 15 mmol/1, in contrast to vasomotor nephropathy, which characteristically has a high urinary sodium content—over 30 mmol/1. If prerenal azotaemia is suspected, a cautious fluid challenge consisting of about 250 ml of crystalloid or colloid infused over 30 min can be tried. If doubt remains about the volume status of the patient, a flow-directed pulmonary arterial catheter should be inserted for accurate assessment of left heart filling pressures.

The urine sediment should be examined carefully. The presence of cellular casts suggests vasomotor nephropathy rather than hepatorenal syndrome. Obstructive uropathy should be excluded by renal ultrasonography or, if necessary, retrograde pyelography.

Treatment

When treating any patient with advanced liver disease, it is essential to avoid factors that precipitate the hepatorenal syndrome. Adequate nutrition must be maintained and electrolyte abnormalities corrected. Diuretics should be used judiciously and ascites drained only for specific indications. Any intercurrent infection must be treated aggressively. The use of certain drugs, such as the non-steroidal anti-inflammatory agents, angiotensin-converting enzyme inhibitors and tetracyclines, should be avoided, and aminoglycosides should not be used unless this is unavoidable.

There is currently no specific treatment for the hepatorenal syndrome; therapy is directed at supporting the underlying liver disease. Haemodialysis and haemofiltration may control the metabolic disturbances of renal failure but the outcome is determined by the degree of liver impairment.

Pharmacological agents that have been used in an attempt to reverse the hepatorenal syndrome include dopamine, isoprenaline, phenoxybenzamine, phentolamine, aminophylline, mannitol, metaraminol, adrenaline (epinephrine), papaverine, and prostaglandin A1. All have been without effect in double-blind studies. Recovery of renal function has occurred following peritoneojugular (LaVeen) and portacaval shunting. Orthotopic liver transplantation appears to offer the best hope for reversal of the hepatorenal syndrome but is only available for a relatively small group of suitable patients.