Autoimmune Hepatitis and Hepatocellular Carcinoma

Briefly noted:

A Tansel et al. Clin Gastroenterol Hepatol 2017; 15: 1207-17.  This systematic review and meta-analysis identified 25 studies and 6528 patients examining the relationship between autoimmune hepatitis (AIH) and hepatocellular carcinoma (HCC) .  In these studies the median followup was 8.0 years.  Key findings:

  • The pooled incidence of HCC was 3.06 per 1000 patient-years
  • 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their diagnosis

My take: This study demonstrates that AIH patients with cirrhosis are at increased risk for HCC.  In patients with AIH who do not have cirrhosis, there does not appear to be a significant risk of HCC.

Also: Link for Online Resource for Hepatopulmonary Syndrome (Canadian Sponsored site). This site has content for patients and for practitioners, including a useful video.


Related blog posts:

Helpful Review on Biliary Atresia

Biliary atresia (BA) remains the leading cause of pediatric liver transplantation and a frequent cause of cholestasis in newborns.  A recent review (AG Feldman, CL Mack. JPGN 2015; 61: 167-75) provides a helpful update. The article begins with a review on pathogenesis, though this remains unknown and continues to be an area of speculation.

The section on evaluation includes a suggested diagnostic algorithm for neonatal cholestasis.  In short, for a 2 week old with jaundice , the authors recommend (STEP 1) fractionating the bilirubin.  The infant is considered cholestasis if the direct bilirubin is ≥1 mg/dL (if total bilirubin is <5 mg/dL) or if direct bilirubin ≥20% of total bilirubin (if total bilirubin is >5 mg/dL).

Among cholestatic infants, the authors recommend (STEP 2) next checking ultrasound and alpha-one antitrypsin (A1AT) (level & phenotype).  The text implies that the authors would check a GGTP.  While this is not in their algorithm, many would suggest checking urine reducing substances, coags, serum glucose, and consideration of sepsis evaluation; these tests can identify issues that are more urgent than identifying biliary atresia.

STEP 3: If U/S and A1AT, are not diagnostic, consider urine culture, urine reducing substances, urine succinylacetone, and additional infectious studies.

STEP 4: Proceed with liver biopsy. If findings of biliary atresia (eg. bile plugs, bile duct proliferation, portal fibrosis), proceed with intraoperative cholangiogram.

Other points:

  • “It is rare for an infant with BA to have a GGTP level <200 U/L.” If low GGTP, consider PFIC, inborn error of bile acid metabolism, and panhypopituitarism.
  • Extensive differential diagnosis table given ((Table 1)
  • “Late diagnosis of BA remains a problem in the United States. The average age of HPE [hepatoportoenterostomy] is 61 days and 44% of patients still undergo HPE after 60 days of life.”  The authors indicate a goal for HPE of taking place  at <45 days of life.
  • Successful HPE can occur even with late diagnosis. 10% to 20% of children who undergo HPE after 100 to 120 days of life still have success in restoring bile flow.”
  • Early/successful HPE is helpful in increasing 10-year transplant-free rate.  Early on, 3 months after HPE, those with a total bilirubin <2 mg/dL compared with those with a total bilirubin of >6 mg/dL have a much lower likelihood of liver transplantation by 2 years of age: 84% vs. 16%.
  • Recommends checking a pulse oximetry at routine followup visits following HPE to look for the possibility of hepatopulmonary syndrome.
  • The article reviews complications including ascites, portal hypertension/GI bleeding, cholangitis, malignancy, and hepatopulmonary syndrome/portopulmonary hypertension.
  • Outcomes: With HPE, “up to two-thirds of patients with BA have short-term clearance of jaundice.” Yet, “80% of patients with biliary atresia will require liver transplantation during childhood.”

Also noted:

“Biliary Atresia is Associated with Hypertension” JPGN 2015; 61: 182-86.

“Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes” A Asai, A Miethke, JA Bezerra. Nat Rev Gastroenterol Hepatol 2015; 12: 343-52.  This review provides in-depth review examines more precise phenotyping, influencing factors (eg. cytomegalovirus), and potential mechanisms.

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From Mt Washburn, Yellowstone

From Mt Washburn, Yellowstone

Expert Recommendations for ARPKD

A recent article (J Pediatr 2014; 165: 611-17) provides expert recommendations for the diagnosis and management of autosomal recessive polycystic kidney disease (ARPKD).

Some of the recommendations relevant to hepatologists:

  • Congenital hepatic fibrosis (CHF) “is presumed when portal HTN [hypertension] is present.”  Portal HTN is defined by splenomegaly (i.e.. spleen >2 cm below the left costal margin or >1 cm larger than ULN for age) and thrombocytopenia with a value of <150 mm3.  Other evidence of portal HTN includes varicose, ascites or hepatopulmonary syndrome.
  • “Liver biochemistries are not typically informative…one should monitor for associated neutropenia and thrombocytopenia.”
  • “Cholangitis may be difficult to diagnose definitively…should be considerd in any child with ARPKD with unexplained fever.” “Routine antibiotic prophylaxis is not indicated…antibiotic prophylaxis for 6-12 weeks after a cholangitis episode..may be considered.”
  • The “use of ursodeoxycholic acid as a choleric cannot be recommended.”
  • Hepatobiliary cancer is not a feature of ARPKD in children
  • “Limiting contact activities in individuals with a palpable spleen is highly controversial and not guided by evidence, but more by common sense.”
  • Recommends annual CBC, ultrasound at five years of age, and then follow-up ultrasound every 2-3 years.

Related blog post:

Pulmonary Complications Associated with Chronic Liver Disease

A useful review of “pulmonary complications in chronic liver disease” (Hepatology 2014; 59: 1627-37) has been published.

The main topics included hepatopulmonary syndrome (HPS) , portopulmonary hypertension (POPH), and hepatic hydrothorax (HH).

A few of the key points:

HPS is most common of these conditions and is identified in 5-30% of cirrhosis patients.  It is identified with abnormal oxygenation (screening with pulse ox <96%) due to intrapulmonary vascular dilatations. There is no established medical therapy.  It is reversible with liver transplantation.

The hallmark of POPH is the development of pulmonary arterial hypertension associated with portal hypertension.  It occurs in 5-10% of cirrhosis patients and often presents as dyspnea on exertion/fatigue.  There are numerous pharmacologic treatments that may be useful, include the following:

  • prostacyclin analogs like epoprostenol
  • endothelin receptor antagonists like boesentan
  • phosphodiesterase-5 inhibitors like sildenafil, vardenafil, and tadalafil

Severe POPH is a relative contraindication for liver transplantation.

HH is a transudative pleural effusion seen in 5-10% of cirrhosis patients. Initial management includes salt restriction and diuretics.  Transjugular intrahepatic portosystemic shunt and thoracentesis are second-line options.  Liver transplantation is curative.

Related blog entries:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.



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:

Portopulmonary Hypertension

A useful update: Liver Transpl 2012; 18: 881-91.

Definition: When pulmonary artery hypertension (PAH), mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, occurs in the setting of of portal hypertension and no alternative cause of the PAH exists (eg, collagen vascular disease, congenital heart disease, or certain drugs), it is known as portopulmonary hypertension (POPH).

  • Mild POPH: MPAP < 35 mm Hg
  • Moderate POPH: MPAP ≥ 35 mm Hg & <45 mm Hg
  • Severe POPH:  MPAP ≥ 45 mm Hg

Patients with moderate POPH and severe POPH, if not improved with medical therapy, have high mortality rates and these are generally considered contraindications for liver transplantation.

POPH is associated with high pulmonary vascular resistance ≥ 240 dyn(sec)(cm¯5 ) and with  pulmonary wedge pressure < 15 mm Hg.

Difference between POPH and hepatopulmonary syndrome:

From the following link: Portopulmonary hypertension and hepatopulmonary syndrome “Abnormal intrapulmonary vascular dilatation, the hallmark of hepatopulmonary syndrome, can cause profound hypoxaemia that can be very difficult to treat. By contrast, portopulmonary hypertension results from excessive pulmonary vasoconstriction and vascular remodelling that eventually leads to right-heart failure.”

Pathophysiology: unclear.  Most but not all cases are associated with cirrhosis.

Frequency: 6-8% of cirrhotic patients.

Diagnosis: while dyspnea may be present, routine screening with echocardiography is part of liver transplantation evaluation.

Prognosis: retrospective study from Mayo clinic (n=74, 1994-2007) noted 5-hr survival of 14% for untreated patients, 45% treated with vasodilators, and 67% who underwent liver transplantation.

Treatments: Table 6 in article.

  • PDE5 Inhibitors (oral): Tadalfil, Sildenafil
  • Endothelin Receptor antagonists (oral): Ambrisentan, Bosentan
  • Prostacyclins (IV): EPO, Trepostinil
  • Prostacyclins (Inhalation): Iloprost , Tyvaso
  • Liver transplantation: 79 patients with LT for POPH 2007-2011

Beta-blockers may have adverse effect.

Noncirrhotic POPH: Worldwide, infection with Schistosoma mansion is likely the most common reason; severe disease may occur in 10% of the 200 million people who are infected.  When noncirrhotic POPH occurs without cirrhosis or Schistosoma mansion, this requires a high degree of clinical suspicion as well as awareness of this disorder.

Additional references:

**Hepatology 2008; 48: 13, 196. POPH: pulmonary arterial htn associated w portal htn:

  • -resting pulm artery pressure > 25mmHg
  • -pulm capillary wedge pressure <15mmHg
  • -pulm vascular resistance >240dynes(s)(cm to -5)
  • -measure c trans thoracic echocardiography
  • -female sex, autoimmune dz were risk factors
  • -avg age associated was 53yrs whereas idiopathic PAH avg age is 36yrs

**NEJM 2008; 358: 2378. Review. Hepatopulmonary Syndrome – New England Journal of Medicine  Hepatopulmonary syndrome, a separate but related condition characterized by hypoxemic respiratory insufficiency due to increased intrapulmonary shunting
**Liver Tx 2007; 13: 680. Hepatopulmonary syndrome experience at CHOA