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Portal Hypertension

The three major and potentially fatal complications of liver disease, namely variceal hemorrhage, hepatic encephalopathy and ascites, are all related to elevation in portal pressure portal hypertension, esophageal varices. Once hepatic sinus portal pressure is increased this results in portal system collapses, varices and variceal hemorrhage. It also results in elevation in ammonia, elevation in neuro-steroid synthesis, which is also hepatic encephalopathy. Finally, the elevated sinus pressure results in renal retention of sodium and ascites. I’ll spend a few moments on neuro-steroids because this is a very recent concept, but I’ll focus most of my talk of variceal hemorrhage.

Now the major inhibitor in the nervous system is GABA, and the dominant modulators of GABA are THDOC, which is tetrahydrodeoxycorticosterone, and tetrahydroprogesterone, which is THP. So these two are the neuro-steroids, and they modulate GABA and cause depression of the central nervous system. The neuro-steroids are synthesized in astrocytes in the brain from cholesterol. This is how they are synthesized. The ammonia goes high, this up-regulates the astrocytic benzodiazepine receptor and this is the major stimulator for neuro-steroid production.

The rest of my talk is on variceal hemorrhage. Portal hypertension occurs when there is elevation either in the resistance to portal flow or increase in portal flow. This results in an elevation in portal pressure and any time the portal pressure goes above 12 mmHg, there is a risk of variceal hemorrhage. How do we decrease this portal pressure? That’s easy enough if you look at the site of dysfunction. Cardiac output is increased in patients with liver disease which results in increased output.

The goals of therapy are first, to decrease the increase in portal pressure and this is what we call "preprimary prophylaxis" to prevent the development of varices. This can be either by decreasing portal flow or decreasing resistance. We don’t have good treatments right now for this, but this s another thing that is going to be addressed in the next millennium.

Who are candidates for primary prophylaxis? They are patients with poor liver function with large varices. That is, these are varices that occupy more than one-third of the lumen and varices that have red weal signs which are longitudinal marks on the varices, which represent a weakness in the wall. Patients with poor liver function, large varices and weal signs.

What are the guidelines for determining the dose of Beta-blockers? You’ve got to use the maximum tolerated dose. I typically use the long-acting version of propranolol, use it in the evening so it lasts for much of the night. The aim of treatment is to reduce the venous pressure gradient, but we monitor these patients to make sure the heart rate decreases by about 25%, or to about 55 beats per minute. The dose is increased every 3-5 days until we reach this goal.

Side effects have rarely been overemphasized, especially in the surgical and endoscopic literature. They occur in less than 15% of patients and generally tend to be mild. Discontinuation is required in about 10% of patients, though the range is quite variable.

Who are the best candidates? The best candidates are those with better liver function but large varices, those who are likely to be compliant and those who have no contraindications to treatment.

So this is what we would recommend as an algorithm in the prevention of variceal hemorrhage. All sclerotics must have an endoscopy. If the varices are small or not present, no treatment, repeat endoscopy in two years. However, if the varices are large, we recommend a baseline pressure monitoring.

Most acute bleeding occurs from the gastroesophageal junction, so it’s important for endoscopists who are looking at these patients to realize that if a patient has a variceal bleed, 85% of the time it is from there. About 10-15% of times it’s in the fundus, and less than 5% of the times it’s above the lower third of the esophagus. So when you treat variceal hemorrhage, this is the area to be treated. Treatment here is often ineffective, and treatment in this area is not required. When a patient has an acute variceal hemorrhage, pharmacological treatment does help.

If endoscopic treatment is used, what’s better? Is it sclerotherapy or ligation? This is a metaanalysis that has been done which shows that ligation is favored in control of variceal bleed and variceal obliteration, but clearly there is a significant difference in re-bleeding risk as well as mortality. And thus, endoscopic ligation remains the best endoscopic way of controlling as well as treating variceal hemorrhage.

So what is the algorithm for a patient you receive with re-bleeding? Start a pharmacological agent, resuscitate the patient and early endoscopy. If it’s a non-variceal cause, treat appropriately. If it’s portal hypertensive gastropathy, we don't have good endoscopic treatment. If it’s gastric varices, or esophageal varices, try controlling it endoscopically. If they re-bleed, repeat the procedure. But if two procedures in 24 hours have not controlled the bleeding, then this is a patient who requires something else, typically a surgical shunt or, much more likely, a transcutaneous intrahepatic portal shunt (TIPS) procedure.