New Paradigm in Treating Varices and Cirrhosis Management (in Adults)

2021 Halloween Pics:

G Garcia-Tsao, JG Abraldes. Gastroenterol 2021; 161: 770-773. Open Access: Nonselective Beta-Blockers in Compensated Cirrhosis: Preventing Variceal Hemorrhage or Preventing Decompensation?

Key points:

  • Carvedilol (not approved in children) is a NSBB that has additional α1 adrenergic blocking activity that enhances the portal pressure–reducing effect, compared to other NSBBs (eg. nadolol, propranolol).
  • New paradigm focuses on “the most relevant end point in compensated cirrhosis…development of decompensation”  (ascites, variceal hemorrhage, and/or hepatic encephalopathy).
  • In the PREDESCI study with 201 patients with compensated cirrhosis and CSPH, with no or small varices, to NSBBs or placebo…”clinical decompensation, was significantly lower in the NSBB arm than in the placebo arm (from 27% to 17% over a median follow-up of 37 months: HR 0.51, 95% CI 0.26–0.97)”
  • This model favors carvedilol over endoscopic variceal ligation; the “only RCT of carvedilol vs EVL in the prevention of first variceal hemorrhage showed a survival benefit of carvedilol over EVL.” Carvediol has been associated with improved survival in patients with cirrhosis (McDowell H.R. et al. Carvedilol is associated with improved survival in patients with cirrhosis: a long-term follow-up study. Aliment Pharmacol Ther. 2021; 5: 531-539)
  • This model “consists of identifying those with CSPH (by means of noninvasive methods) and treating them with carvedilol, with the goal of preventing any decompensating event (not only variceal hemorrhage).”
  • Screening endoscopy would still be recommended in newly-diagnosed decompensated cirrhosis and those intolerant to NSBBs.

My take: This new paradigm is one approach for portal hypertension in adults. More studies are needed in the pediatric age group to help determine whether medical therapy can obviate the need for EVL in most children with cirrhosis.

Whereas the existing paradigm focuses on the use of NSBBs for the prevention of variceal bleeding, in the new paradigm the presence of CSPH [clinically significant portal hypertension ](determined noninvasively) establishes the indication for NSBBs with the goal of preventing cirrhosis decompensation. CSPH, clinically significant portal hypertension; EVL, endoscopic variceal ligation; NSBB, nonselective beta-blocker; LS, liver stiffness; PLT, platelet count. ∗Patients with LS <20 kPa and PLT >150,000/mm3 can circumvent endoscopy because the risk of having high-risk varices is minimal

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

#NASPGHAN19 Liver Symposium (Part 3)

Although I was unable to attend this year’s liver symposium at NASPGHAN19, I reviewed the lecture notes.  There is some terrific content.  Here are some of the slides (borrowed with permission from NASPGHAN).

Link to complete NASPGHAN Chronic Liver Disease Symposium 2019


What do I do now? The management of portal hypertensive complications: Varices, ascites, and encephalopathy Rene Romero, MD, Children’s Hospital of Atlanta

When there is good function, but the flow is all wrong: Approach to non-cirrhotic portal hypertension Evelyn Hsu, MD, Seattle Children’s Hospital

The role of the interventional radiologist in the treatment of portal HTN: How can I help you?  Jared R. Green, MD, Ann and Robert H. Lurie Children’s Hospital (SLIDES NOT AVAILABLE)

When to consider surgery in the treatment of portal HTN?  Riccardo Superina, MD, FRCS(C), FACS, Northwestern University  (SLIDES NOT AVAILABLE)

What is the role for preventing variceal bleeding in Biliary Atresia?

During medical school, I read a book called “The House of God”  (The House of God – Wikipedia, the free encyclopedia.  One of this cynical book’s premises is that doing more diagnostic tests and treatments to help patients actually harms them.

A recent study of children with biliary atresia reminded me of this premise (Gastroenterol 2013; 145: 801-7, eidtorial 719-22).   In this retrospective study, there were 66 children with endoscopic evidence of portal hypertension who underwent endoscopic therapy for either primary (n=36, mean age 22 months) or secondary (n=30, mean age 24 months) treatment of esophageal varices biliary atresia (2001-2011).  These children were at high risk for bleeding; they had a mean bilirubin of >10 mg/dL and 20% had ascites.


Primary prophylaxis group: mean of 4.2 sessions were needed to eradicate varices.  Varices reappeared in 37%; there was no breakthrough bleeding.  97% survived for 3 years.  All of these patients had varices grade 2 or higher and 94% had red wale markings.

Secondary prophylaxis group (after previous bleeding): mean of 4.6 sessions to eradicate varices.  Varices reappeared in 45% and 10% had breakthrough bleeding.  84% survived for 3 years.


  • For bleeding group, sclerotherapy was used in 73%, banding in 17%, and both in 10%.
  •  For prophylaxis group, sclerotherapy was used in 44%, banding in 41%, and both in 14%.
  • By the end of the study, sclerotherapy was mainly used in patients weighing less than 8 kg.
  • Each endoscopy session had the same endoscopist, used octreotide (2 mcg/kg/hr) an 1 hour before and then for 2-3 days afterwards.
  • With bleeding patients, these sessions occurred after the patient was stabilized, with a mean of 10 days afterwards.
  • Patients had an average of four 3-day hospitalizations.
  • Within an average of 14 months, more than half of the primary prophylaxis group had undergone transplantation

The authors interpret their data as follows:  “primary or secondary prophylaxis of bleeding is well tolerated and greatly reduces the risks of variceal bleeding in children with biliary atresia and high-risk gastroesophageal varices.  The results support the active detection of these signs by endoscopic procedures.”

In contrast, the editorial is much less supportive of primary prophylaxis.  “We need to weigh the risks and benefits of multiple procedures in a nonbleeding child who may not bleed for years, when varices have a high chance of recurring and transplant is sometimes imminent. Because mortality from gastrointestinal bleeding in children is quite low (zero in this small study), we may need to consider a ‘wait and see’ approach.”

Bottomline: A failed Kasai is an indication for transplantation which is a much more definitive treatment for portal hypertension.

Previous related blog posts:

Transfusion strategy in acute GI bleeding

A recent study shows that holding off on blood transfusions can improve survival with severe acute upper gastrointestingal bleeidng (NEJM 2013; 368: 11-21).  This finding is not unexpected as this has been shown in observational studies.  In addition, in critical care patients without acute GI bleeding, a restrictive approach to transfusions has also been beneficial.

This study which enrolled 921 patients (>18 years) assigned 461 to a restrictive transfusion strategy (transfusion if <7 g/dL or at discretion of physician) and 460 to a “liberal” strategy (transfusion if <9 g/dL).

In additon to fewer transfusions, the restrictive group had improved survival:

  • 225 in the restrictive group did not require a blood transfusion compared with 65 in the liberal group
  • Survival at 6 weeks: 95% in the restrictive group compared with 91% in the liberal group.  Hazard ratio 0.55 (confidence interval 0.33 to 0.92) –a 45% reduction in the relative risk of 45-day mortality.
  • Recurrent bleeding occurred in 10% of the restrictive group compared with 16% of the liberal group.
  • The patients with cirrhosis (and Child-Pugh class A or B) were most likely to benefit from a restrictive approach with hazard ratio of 0.30.  Child-Pugh class C did not have a benefit from a restrictive approach with hazard ratio of 1.04.  With the liberal approach, there was a higher portal-pressure gradient within the first five days.

The reasons for bleeding in this study included peptic ulcers in about 50%, and varices in 24%.  The other causes included Mallory-Weiss tears, erosisve gastritis/esophagitis, and neoplasms.

Why does giving less blood result in better outcomes?

  1. Transfusion may impair hemostasis in several ways.  It may result in abnormalities in coagulation properties.  It may counteract splanchnic vasoconstrictive response.  And, in those with cirrhosis, it can increase portal pressure (even in the presence of somatostatin).  All of these mechanims may increase rebleeding.
  2. In addition, systemic effects from transfusion can include circulatory overload and pulmonary edema.

Also (unrelated to this posting), a thoughtful comment to a recent post on FDA regulations was posted by Ben Gold (Can the FDA prohibit free speech? | gutsandgrowth).

Related blog references:

Expert advice on portal hypertension

A consensus report on portal hypertension has helpful advice on a broad range of management issues and should be kept in mind as a handy reference (Pediatr Transplantation 2012; 16: 426-37).  The report is concise and full of bullet points.  It is based on a meeting of pediatric experts to modify adult guidelines (Baveno V) for pediatrics.

In many instances, the experts indicate that there is not enough pediatric data. Specific subjects include the following (along with some points):

  • Treatment options for portal hypertension -consider screening for varices if thrombocytopenia and splenomegaly.  ‘No indication to use beta-blockers to prevent varices.’
  • Prevention of first bleeding episode -in the presence of varices (grade II or III), variceal ligation reasonable in selected children and/or within context of defined research protocols. Grade I varices can be flattened with insufflation, and grade III varices are confluent around circumference of esophagus (per Japanese Research Society for Portal HTN analysis)
  • Role of hepatic venous pressure gradient measurement (HVPG) -‘panel was undecided as to whether HVPG measurements in children’ should be ‘part of specialized clinical practice or’ a research tool.
  • Blood volume restitution -suggests use of platelets in cases of bleeding with profound thrombocytopenia (<20,000).
  • Antibiotic prophylaxis -unclear whether empiric antibiotics in children are needed in the presence of variceal bleeding.
  • Management of treatment failures -can retry endoscopy and if fails, consider transjugular intrahepatic portosystemic shunting (TIPS)
  • Management of gastric varices -only case reports in children, thus no evidence-based recommendations.
  • Prevention of rebleeding -variceal ligation (EVL) preferred in patients with cirrhosis.  EVL should be performed every 2-4 weeks up to five sessions to eradicate varices after 1st bleed.
  • Treatment of portal vein obstruction -diagnosis, natural history, anticoagulation, use of MesoRex bypass procedure, associated portal biliopathy -diagnosis and treatment.  With regard to MesoRex, ‘controversy exists as to the appropriateness of ..this procedure in an asymptomatic child.’ Surveillance endoscopy may assist in decision-making.
  • Hypersplenism with portal vein obstruction-in the presence of platelet count <50,000 and portal vein obstruction, strong consideration should be given to MesoRex procedure.
  • Portopulmonary hypertension and hepatopulmonary syndrome -important to monitor oxygen saturation in patients with portal vein obstruction/other causes of portal hypertension. If <97%, additional investigation may be needed.  Portopulmonary hypertension is best characterized with cardiac catheterization and hepatopulmonary syndrome with saline echocardiography.
  • Other topics: Prevention of hepatic encephalopathy, managing bleeding episodes, endoscopic treatment

Related blog entries:

Learning a lot from ChiLDREN (part 2)

As noted in previous post (Learning a lot from ChiLDREN (part 1) | gutsandgrowth), several recent studies highlight the benefits of multisite collaboration to study infrequent pediatric liver problems.  In these studies, the Childhood Liver Disease Research and Education Network (ChiLDREN) has collected prospective longitudinal observational date from multiple centers; data from 10 centers provides useful information on the frequency of portal hypertension (PHT) in young adults with biliary atresia (BA) (JPGN 2012; 55: 57-73).

163 subjects were enrolled between May 2006 and December 2009.  Seven patients were excluded due to the presence of polysplenia which interferes with the assessment of PHT.

Demographics: subjects ranged in age from 1 to 25 years with a mean of 9.2 years.  56% were female, 75% were caucasian.

PHT was considered definite if there was either a history of a PHT complication (variceal bleeding, ascites) or if there were clinical findings c/w PHT (both splenomegaly and thrombocytopenia).  PHT was considered “possible” if either splenomegaly or thrombocytopenia was present and “absent” if no criteria were met.

  • PHT: definite in 80 (49%), possible in 27 (17%) and absent in 56 (34%)
  • 43 subjects had a history of PHT complications: 32 with esophageal variceal (EV) bleeding, 14 with ascites, and 8 with hepatopulmonary syndrome.
  • Of the patients with EV, only 3 had normal platelet count and normal spleen size.

Teaching points:

  1. One-third of subjects with EV bleeding survived with their native liver for at least 5 years.
  2. EV age of onset was highly variable; 7 had bleeding in the first two years of life.
  3. Growth parameters were fairly unremarkable in those with definite PHT.
  4. Long-term followup will be needed to identify factors which predict progression of PHT and the development of adverse outcomes.

Previous related blog posts:

All bleeding stops

Although the title is technically true, there are preferred ways to stop GI bleeding (Clinical Gastroenterol & Hepatol 2012; 10: 234-39).  This article summarizes the approach for nonvariceal upper GI bleeding.


  • Endoscopy within 24 hours following ABCs/adequate resuscitation.  Use of a promotility agent prior to endoscopy may be helpful (in pediatric patients: erythromycin ~3 mg/kg)
  • Correct coagulopathy but do not delay endoscopy.
  • Consider nasogastric tube placement.
  • Do not use somatostatin or octreotide.
  • High-risk endoscopic stigmata should receive endoscopic hemostasis.  These lesions include actively spurting, oozing blood, nonbleeding visible vessel, and an adherent clot.
  • Pigmented dots or clean base ulcers do not require endoscopic hemostasis.
  • Endoscopic management includes clips, thermocoagulation, or sclerosant injection alone or in combination with epinephrine injection.  Epinephrine alone is not recommended for high risk lesions.
  • If a clot is found, attempts to remove it should be made to visualize underlying lesion.  If clot is adherent, intensive IV PPI therapy may be sufficient.  A typical dose would be esomeprazole 80mg bolus (for an adult) followed by 8 mg/hour for 72 hours.
  • Stable patients can be fed within 24 hours.
• IV PPI dose: 1mg/kg bolus followed by 0.1mg/kg/hr infusion.

Additional references:

  • -Ann Intern Med 2010; 152: 101-113. Consensus recommendations on UGI bleeding. Early endoscopy (<24hrs), data support attempts to dislodge clots, consider clips or thermocoagulation for Rx. Preendosocpy PPI can be helpful.
  • -Clin Gastro & Hep 2010; 8: 651. Article suggests second look only if difficult visualization on initial endoscopy (eg unable to remove clot).
  • -Ann Intern Med 2010; 152: 101-13. Systematic review of on UGI bleeding. Use IV PPI bolus, then continuous PPI if high risk stigmata after endoscopic Rx. Hospitalize for at least 72hrs.
  • -Gastroenterology 2010; 138: 1252. Review of upper GI bleeding.
  • -Clin Gastro & Hep 2009; 7: 828. Review of recurrent GI bleeding with negative initial evaluation.
  • -Gastroenterology 2008; 134: 1836. Frequent high dose oral PPI also effective with bleeding ulcers: prevacid 120mg x1, then 30mg q3hrs compared favorably with 90mg IV followed by 9mg/hr. n=66. intragastric pH >6 for 68% of study in IV PPI vs. 65% in oral PPI. 1st hour -more rapid onset with IV PPI.
  • -Gastroenterology 2007; 133: 1694. Position statement & review on obscure bleeding.
  • -Ann Intern Med 2003; 139: 843-857. Consensus on nonvariceal bleeding. Rec: lansoprazole 90mg bolus, then 6mg/hr x 72hrs or pantoprazole 80mg then 8mg/hr in high risk lesions
  • -Clin Gastro & Hep 2006; 4: 1459. Trends in non-variceal bleeding between 1993-2003 do NOT show improved outcomes with PPI. Overall mortality fairly steady @3.5%
  • -Clin Gastro & Hep 2005; 3: 959. WCE should be 2nd step in obscure bleed, p egd/col.
  • -NEJM 2004; 351: 488. case review.
  • -Gastroenterology 2002; 123: 17-23. IV erythromycin, 20 minutes before endoscopy, helped clear stomach (82% clear vs. 33% c placebo). Adults in this study received 250 mg. (thus, children probably need 3-4 mg/kg)
  • -Gastro Endosc 2002; 56: 174. erythromycin helpful-3mg/kg IV over 30 min
  • -Gastroenterology 2002; 123: 407-13. Endoscopic Rx of adherent clots c PUDz helpful (epinephrine injection, cold guillotining of clot, then coagulation cautery); Editorial on 632-635 emphasizes vigourous washing BUT NOT to remove adherent clot unless in centers with low rebleeding rates. Additionally, PPIs very helpful in preventing rebleeding in this situation (NEJM 1997; 336: 1054-8).
  • -NEJM 1999; 341: 38. Occult bleeding
  • -Gastroenterology 2000; 118: 197. AGA position statement.
  • -Gastro Endosc 2001; 53: 853 & 859. ASGE guidelines/algorithm for upper & lower GI bleeding