Category Archives: Pediatric Gastroenterology Liver Disease

How to stop HBV vertical transmission

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A review and a study this month help delineate a strategy to lower the rate of HBV transmission (Clin Gastro Hepatol 2012; 10: 452-59 & 520-526).  Overall, using HBIG and HBV vaccine within 12 hours of birth (followed by two additional doses of vaccines within 6-12 months) prevents about 95% of HBV transmission from HBsAg-positive mothers to their infants.  This has made a huge difference.  Yet, among mothers with high levels of viremia, HBV is still transmitted in 8-30%.  As such, this review proposes an algorithm to reduce mother to child transmission (MTCT).

The key risk factor is HBV DNA levels >200,000 IU/mL; the most effective way to reduce transmission from highly-viremic mother to infancts is the use of antiviral therapy.  The authors recommend that in addition to the usual preventive measures (HBIG/HBV vaccine within 12 hours of birth), that efforts to lower MTCT include use of either lamivudine (pregnancy category C), telbivudine (pregnancy category B), or tenofovir (pregnancy category B) at the 3rd trimester in the following:

  • Infected women with high HBV DNA levels
  • Infected women who have had children who have failed previous prophylaxis
  • Infected women with threatened pre-term labor

In addition, elective C-section should be considered if HBV DNA >20 million IU/mL at full term.

The second citation refers to an open-label prospective study of 88 HBe-Ag positive women.  All women had HBV DNA >6 log10 copies/mL and increased ALT.  Telbivudine (600 mg/day) was administered to 53 women starting between 12 and 30 weeks gestation; there were 35 control patients who all received HBIG/HBV vaccine.  In the treatment group, none of the infants developed HBV infection.  In the control group, the transmission rate was 8.6%.  No significant adverse effects were noted; specifically, no congenital malformations were noted.

Related blog entry/additional references:

Diagnosing biliary atresia earlier

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Biliary atresia (BA) is often suspected among infants with prolonged jaundice. In fact, efforts have been underway for a long time to encourage fractionation of the bilirubin values to look for conjugated hyperbilirubinemia, especially in infants that remain jaundiced at three weeks of life.  While this is still good advice, given the lack of success in implementation, there is good evidence that obtaining a fractionated bilirubin at any time point can help identify cholestasis associated with BA.

A recent article by Karpen et al (Pediatrics 2011; 128:. e1428 -e1433) indicates that direct bilirubin values are elevated beginning within the first one to two days in patients with BA.  In their cohort of 61 BA subjects, 56% had newborn fractionated bilirubin values.  Every BA patient had elevated direct bilirubin, on average 1.4 ± 0.43 mg/dL (normal <0.5) (compared with control patients:  0.19 ± 0.075 mg/dL, P < .0001).  Also, another important finding was that early on the ratio of direct bilirubin to total bilirubin was normal in 79%; normally this ratios is ≤0.2.  As such, all patients with increased direct bilirubin need to be followed closely.

Related blog entries:

Outcomes of Biliary Atresia

MicroRNAs and biliary atresia

Bleeding due to vitamin K deficiency

Bleeding due to vitamin K deficiency

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With cholestasis in infancy, Bill Balistreri taught me that there were four potential emergencies:

  • Bleeding due to vitamin K deficiency or coagulopathy
  • Hypoglycemia
  • Sepsis
  • Metabolic poisoning with formula (in patients with galactosemia)

Once these issues have been considered, then it is appropriate to start investigating the etiology of the cholestasis.

One of the more dramatic complications is intracranial hemorrhage (ICH). While ICH is a well-recognized complication of cholestasis in infancy, the long-term outcomes are not well-characterized. A report from Japan adds some insight (JPGN 2012; 54: 552-57).

Among a retrospective review of 83 infants with biliary atresia (BA) between 1979 to 2009, ICH occurred in 8% despite oral vitamin K prophylaxis (2 mg).  The onset of ICH was between 47-76 days after birth and was prior to surgery.  Coagulopathy was noted in all cases, which improved with vitamin K intravenously.  Two infants required craniotomy.  In 5 of 7 cases, neurologic sequelae were noted including developmental delay in three, epilepsy in one, and mild hemiparesis in two.

Additional references:

  • Blood Rev 2009; 23: 49-59.  Review of vitamin K deficiency.
  • Pediatrics 2008; 121:e857.  Vitamin K deficiency common in cholestatic breastfed babies.  Can be prevented with 1mg po each week or single IM dose of 2mg.
  • Eur J Pediatr Surg 2005; 15: 295-9.  Bleeding disorder as 1st symptom of BA.
  • Pediatr Neurosurg 2006; 42: 362-7.  ICH due to vitamin K deficiency.
  • Pediatrics 2006; 118: e1657.  dose of 0.2mg effective for median of 25days (w/o toxicity/accumulation of K1O) in infants <32weeks gestation.

Increased ferritin predicts poor response in Hepatitis C

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Serum ferritin levels were independently shown to be a risk factor for poor response to treatment in hepatitis C virus (HCV) infection (Hepatology 2012; 55: 1038-47).  This article adds additional information to previous work which has shown that increased iron can be a comorbid factor in chronic viral hepatitis and other liver diseases.

This study used the Swiss Hepatitis C Cohort Study (SCCS) (n=3648).  In this group, the success of treatment with pegylated interferon alpha and ribavirin were correlated with clinical and histological features.

Ferritin levels ≥ the sex-specific median values was one of the strongest pretreatment predictors of treatment failure (OR 0.45). It had a similar predictive effect as the IL28B genotype.  In addition, higher ferritin levels were associated with severe liver fibrosis (OR 2.67) and steatosis (OR 2.29).  For women the sex-specific median for ferritin level was 85 μg/L and for men it was 203 μg/L.  The authors note that these cutoffs are quite close to the upper limits of normal of the general population (150 and 300 respectively).

Mechanistically, HCV interferes with the host’s iron metabolism leading to iron accumulation in the liver.  Part of this is explained by down-regulation of hepcidin (Help with hepcidin).  Part is due to ferritin acting as an acute phase reactant to inflammation.  Ultimately, excess iron promotes liver inflammation, oxidative stress and mitochondrial dysfunction.

How important ferritin will be with newer therapies is not clear.  It is likely that patients that are less responsive to dual therapy (pegylated interferon/ribavirin) will have poorer response as well to triple or quadruple therapies.

Additional references/previous related posts:

Good care 24/7

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In hospital settings, there have been concerns about clinical care at night or weekends (see references below).  At least with liver transplantation, 24/7 care appears to be the rule rather than the exception (Liver Transpl 2012; 18: 558-65). 

Using the UNOS database, this study analyzed 94,768 transplants from 1987-2010.  Survival rates at 30, 90, and 365 days for nighttime operations: 96%, 93%, and 86% respectively.  For weekends, the respective rates were 95%, 92%, and 86%.  These rates did not differ from weekday rates.  Graft failure rates were modestly increased for weekend transplants at 365 days (HR 1.05, 95% confidence interval 1.01-1.11) but not for 30 days or 90 days.  In addition, there was no difference in graft failure between nighttime and weekday transplantations.

Additional reference:

  • -Clin Gastroenterol & Hepatol 2009; 7: 296., 303.  n>400,000 discharges.  OR 1.2 for mortality of UGI bleed if on weekend. 
  • NEJM 2001; 345: 663-668.   3,789,917 admissions (in Canada).  Weekend admissions were also associated with significantly higher mortality rates for 23 of the 100 leading causes of death and were not associated with significantly lower mortality rates for any of these conditions.

Proton pump inhibitors–infection risk with cirrhosis

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In a previous post (The Medical Pendulum and Gastroesophageal Reflux), I note that enthusiasm for proton pump inhibitors has started to wane.  In addition, a significant number of reported of potential side effects were referenced.  Another potential adverse effect is increasing the rate of spontaneous bacterial peritonitis (SBP) in patients with cirrhosis (Clin Gastroenterol Hepatol 2012; 10: 422-27).

This retrospective study examined 65 hospitalized cirrhotic patients with paracentesis-proven SBP between 2006-2009 and compared them to 65 contemporaneous hospitalized cirrhotic patients without SBP.   Patients with SBP had a higher incidence of use of PPI within previous 7 days: 71% versus 42%.  Of patients with SBP receiving PPI, the authors state that 68% did not have a documented indication for PPI use.

Additional references/previous posts:

  • –Treating reflux does not help asthma
  • -Risk of Hypomagnesemmia -2011. http://www.fda.gov/drugs/drugsafety/ucm245011.htm
  • –Gastroenterology 2010; 139: 1115.  Review of safety of PPIs.
  • –Gastroenterology 2010; 139: 93. n=167,000. PPIs associated with hip fracture risk, OR 1.3, in patients with other risk factors.
  • –Gastroenterology 2010; 138: 896-904. 5 yrs of PPI -no increase risk in hip/spine fx.
  • –Arch Intern Med 2010; 170: 765-71, 747 (ed). PPI not related to hip fx (n=161,806) women 50-79. INCREASE risk of spine fx, hazard risk 1.47
  • –Arch Intern Med 2010; 170: 772-8. PPIs increase risk of Clostridium difficile infection (hazard ratio 1.42 –42% increase in risk), n=1166.
  • –Arch Intern Med 2010; 170: 784-90. n=101,796. OR 1.74 for daily PPI, OR 2.36 if BID Rx; thus ~70% increase risk of nosocomial infection.
  • –Clin Gastro & Hep 2010; 8: 504. Increased bacterial overgrowth with PPI use.
  • -JAMA 2009; 301: 2120-2128. Use of PPIs associated with INCREASED hospital acquired pneumonia by ~30%. Could result in 180,000 HAP cases/yr with ~33,000 deaths. n+ 63,878 admissions, 52% on PPIs or H2RAs (83% PPIs, 17% H2RAs). H2RAs NOT associated with HAP cases.

Picking winners and losers with liver transplantation allocation

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From a pediatric hepatology viewpoint, I’ve always been concerned that scoring systems  do not favor children.  More data is now available relevant to this topic:

  • Goldberg et al. Liver Transplantation 2012; 18: 434-43, editorial: 381-83 
  • Sepulveda et al. Liver Transplantation 2012; 18: 413-422, editorial: 389-90

These articles and the editorials look at the model for end-stage liver disease (MELD) and exceptions for hepatocellular carcinoma (HCC) as well as the issue of split livers to expand the donor pool.

The goals of liver transplantation allocation is to distribute livers to  minimize waiting list mortality, to distribute this valuable resource fairly, and to improve long-term outcomes.  How are we doing?

With regard to HCC, the authors indicate that the current policy is increasing the number of individuals transplanted with this indication.  Before MELD, 4.6% of all transplants were for candidates with HCC.  Between 2002-2007, the number increased to 26%.  This has dramatically improved the outcomes in this previously almost universally fatal disease.

But is the priority afforded by MELD priority unfair?  From 2005-2009, Goldberg et al show that the rate of individuals with HCC removed from the waiting list because of death or disease progression was much lower than non-HCC patients: 4.2% vs. 11% (90-day waitlist outcome).  Patients with HCC with exception points were 2.62 times less likely to die by waiting.  Thus, the authors conclude that allocating 22 MELD points to HCC patients greatly overestimates 90-day mortality.  Other conditions that receive 22 MELD points include candidates with hepatopulmonary syndrome, cholangiocarcinoma, cystic fibrosis, familial amyloidotic polyneuropathy, and portopulmonary syndrome.

Sepulveda et al performed a retrospective review of the experience from split liver transplantation in French adults.  In their cohort of 36 patients who received extended right grafts from split livers, there were increased complications.  Only 21 patients had a relatively easy postoperative course.  Six patients required retransplantation.  Overall survival rate was 84.2% and 77.7% at 1 and 5 years.  Complications were related to ischemia of hepatic segment 4.

In the editorial, Riccardo Superina makes several important points:

  • Many centers have equivalent outcomes for whole and split livers; there is likely a learning curve to improve technique.
  • In the U.S., between 2002-2009, only 288 split livers grafts were performed in adults whereas there were >29,000 whole liver transplants performed.
  • In the U.S. children have the highest mortality rates on the waiting list.  In 2008, 18% of children died without a chance for liver transplantation.
  • In France, allocation policy dictates that livers from all donors less than 30 years old should be directed to children first with the stipulation of liver splitting.  If this policy were adopted in US, it could alleviate the organ shortage for children who are currently most disadvantaged by UNOS (United Network for Organ Sharing) allocation policy.

Related blog posts:

Big gift, how much risk

Sarcopenia, fatigue, and nutrition in chronic liver disease

A liver disease tsunami

Additional references:

  • -Am J Transplant 2010; 10: 1643-48.  HCC patients advantaged with current allocation
  • -Clin Gastro & Hep 2008; 6: 1255. solutble TNF receptor 75 better at predicting mortality risk than MELD>
  • -Gastroenterology 2008; 135: 1568. MELD has changed allocation -less-ill patients now getting higher risk organs.
  • -Liver Transplantation 2006; 12: S128-S136. Guidelines for exceptions (increased status)
  • -Liver Transplantation 2006; 12: 12-15, 40-45. 53% of pediatric livers allocated based on other factors (eg. exception, status 1) than PELD score
  • -Gastroenterology 2003;124: 91-96, 251. MELD scores works fairly well in adults; factors in bilirubin, INR, creatinine.

Diagnosing autoimmune hepatitis

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Criteria for autoimmune hepatitis (AIH) have been simplified over the last decade.  The 2008 AIH criteria have a high sensitivity and specificity in children (Clin Gastroenterol Hepatol 2012; 10: 417-21).

This study examined 238 patients: 41 AIH patients and 197 non-AIH patients.  Among these patients, 37 of the 41 AIH had sufficient data to calculate 2008 score using IgG or globulin & 40 of the 197 of the non-AIH had sufficient data.  Within the 37 AIH patients, 31 had IgG levels; all 37 had either IgG or globulin.  Similarly, among the 40 non-AIH patients, 26 had IgG levels available.

Among AIH patients:  the 1999 criteria categorized 29 of 31 (94%) as definite AIH and 2 of 31 (6%) as probable AIH.  The 2008 criteria: 25  definite AIH, 2 as probable AIH, and 4 were not identified as AIH; all four had fulminant hepatic failure (FHF).

The authors conclude that the simplified 2008 guidelines have high sensitivity/specificity and are easier to use.  Patients with FHF require the 1999 criteria.

  • -Hepatology 2008; 48: 10, 169. Simplified diagnostic criteria: points for autoabs, IgG, histology, & absence of viral hepatitis.

Autoantibodies:

ANA or SMA 1:40                  1
ANA or SMA 1:80
or LKM
or SLA 1:40                           2*

IgG:
IgG >Upper normal limit        1
>1.10 times ULN                   2

Liver histology (evidence of hepatitis is a necessary condition)
Compatible with AIH             1
Typical AIH                            2
Absence of viral hepatitis      2

Scoring Total:

>/=6: probable AIH
>/=7: definite AIH
*Addition of points achieved for all autoantibodies (maximum, 2 points).

Additional references on AIH criteria:

  • -Clinical Gastro & Hep 2011; 9: 57, 3 (editorial). Many AIH meet criteria w/o liver biopsy.
  • AIH 1999 criteria:  Hepatology 2009; 50: 538. diagnosis with scoring system vs. simplified. 1999 criteria more precise. See page 539 for details:

Scoring (points in bold):
if female gender,  +2
if ALP: AST (or ALT) less than 1.5, then +2
if globulin >2 (+3), +2 if >15, +1 if >1
if ANA, >1:80 +3, 1:80 =2, 1:40 +1
if neg viral markers, +3
drug hx neg, +1
if alcohol <25g/d, +2
liver histology: if interface hepatitis +3, lymphoplasmacytic infiltrate +2
if autoimmunity in pt or 1st degree relative, then +2
if response to Rx, +2
Interpretation: if pretreatment >15 definite AIH, 10-15 probable
if posttreatment: >17 definite, 12-17 probable

Additional AIH references:

  • -Gastroenterology 2011; 140: 1980. n=229. in single center, 93% achieved NL ALT w/in 12 months –though still with increased mortality compared to general population.
  • -Liver Tx 2011; 17: 393. 86% 5yr pediatric (n=113) OLTx survival (same as entire cohort)
  • -Hepatology 2010; 53: 926. AIH steroid failures (~20%) more likely to have worse disease at presentation. n=72
  • NAPGHAN 2010 Pointers:  Rx: Typical prednisone dose is 2 mg/kg/day, max 60 mg/day (“Mieli-Vergani regimen”). 90% of patients have dramatic improvement in LFTs within 2 weeks of starting corticosteroids, 80% achieve in remission in ≤18 mos. For the 10-20% failure rate, consider non-adherence to medications or make sure that you have the right diagnosis. Most children with AIH require prolonged or indefinite treatment with steroids, albeit at low dose
  • -Hepatology 2008; 48: 863. n=243. Risk factors for HCC in AIH. Main risk is cirrhosis with HCC occuring ~102 months after cirrhosis develops
  • -Hepatology 2010; 52: 2247. Suggested protocol to minimize steroids: Combined Azathioprine (~1.5/kg in adults) with steroids. Use steroids for 3 months then taper to 5-10mg/day. If doing well, try to d/c steroids at 1 yr of Rx.
  • -JPGN 2010; 51: 524. Use of allopurinol when Azathioprine toxicity (3 cases). Allopurinol dosed between 25mg-50mg and Azathioprine reduced to 0.5-1mg/kg/day.
  • -Hepatology 2008; 48: 10, 169. Simplified dx criteria: points for autoabs, IgG, histology, & absence of viral hepatitis.
  • -Hepatology 2008; 47: 9494-57. Asymptomatic PSC common in AIH –might be higher than 10%.-Clinical Gastro & Hep 2008; 6: 379. genetic factors affecting phenotype of AIH.
  • -Clin Gastro & Hep 2008; 6: 1036. Use of cellcept/mycophenolate for AIH.
  • -JPGN 2006; 43: 635. Use of cyclosporine initially for 6 months, then changing to AZA/steroids, n=84. Goal of CYA trough 250 +/- 50 for 1st 3 months.
  • -Hepatology 2006; 43: (Suppl 1): S132. Nice review.
  • -NEJM 2006; 354: 54. AIH Review.
  • -Clin Gastro & Hepatology 2004; 2: 935. Reviews AIH/PSC criteria in children; use of GGT recommended.

Variability in Inborn Errors of Bile Acid Metabolism

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There is significant variability in the presentation of the most common inborn error of bile acid metabolism, 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) deficiency (Molho-Pessach V et al, Hepatology 2012; 55: 1139-45).  

This report investigated a 24-year-old women from Iran with idiopathic cirrhosis and a strong family history of idiopathic cirrhosis, as well as a 32-year-old first-cousin who had a self-limited liver disease (resolved at age 9).  A genome-wide analysis of 2.4 million single nucleotide polymorphisms was performed in the patient and cousin and compared to a healthy relative.  The investigators were able to identify regions of homozygosity  that was present in the proband and cousin but not the healthy relative; one of these regions corresponded to a gene encoding 3β-HSD.  Subsequent, sequence analysis revealed a specific frameshift mutation and high levels of 3β-hydroxy-Δ5 using mass spectrometry.

For me, this report has two take home points:

  • As with a lot of diseases, 3β-HSD can have variable phenotypic expression and may present beyond infancy.  Its diagnosis remains important because a timely diagnosis allows effective treatment with bile acid replacement.
  • More ‘idiopathic’ diseases will be unmasked with new molecular tools, especially when investigators combine these tools with careful history-taking and family history.

Additional references:

  • w/u for bile acid defects: FAB-MS fast atom bombardment mass spectrometry
    **stop URSO 5 days before test
  • http://www.orpha.net/data/patho/Pro/en/InbornErrorsBileAcidMetabolism-FRenPro11194v01.pdf. Online review article from Heubi JE, et al, reprinted with permission from Thieme Medical Publishers (Seminars Liver Dis. 2007 Aug;27(3):282-294) Homepage at www.thieme.com.“At the Cincinnati Children‘ Hospital Medical Center, more than 130 patients have been identified with defects, accounting for 1% to 2% of the cases of unexplained liver disease in infants and children.”
  • -Gastroenterology 2009; 137: 1310.  Long-term good efficacy of cholic acid for primary defects in bile acid synthesis.
  • -Hepatology 2009; 39: 1403.  Review defects in bile acid synthesis.

When death is on the line

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“Never go against a Sicilian when death is on the line“! –from The Princess Bride

With acetaminophen-induced hepatic failure, King’s College Hospital (KCH) Criteria have been helpful for predicting death.  While the Sequential Organ Failure Assessment (SOFA) was not designed by a Sicilian (to the best of my knowledge), it is more sensitive at predicting death than KCH Criteria (Liver Transplantation 2012; 18: 405-412, & editorial 384-86) .

SOFA measures organ dysfunction by evaluating each of the following on a 0-4 scale: respiratory, hepatic, coagulation, cardiovascular, neurologic, and renal.

In the cited study, 125 consecutive adult patients (mean age 38 years) with acetaminophen-induced acute liver failure were evaluated.  KCH criteria had highest specificity (83%) and lowest sensitivity (47%).  The SOFA score had the best discriminative ability.  A SOFA score >7 during the first 96 hours predicted death or transplantation with a 95% sensitivity and 70.5% specificity.  Other specific predictors of poor outcome included higher lactate levels, worsened coagulation parameters, and need for mechanical ventilation.  In this cohort, 67 (54%) survived with medical management, 35 (28%) died and 23 (18%) received a liver transplant.

While sensitivity and specificity will vary based on pretest probability/specific population, what is clear is that relying on KCH criteria alone would be unwise.

Additional references:

  • -J Pediatr 2011; 159: 813.  Study of ALF in young infants.  38% were indeterminate, ~14% NH, 12% herpes.  n=148. 60% survived w/o OLT, 24% died, 16% OLT
  • -Hepatology 2010; 53: 567.  18% of indeterminate ALF may be due to acetaminophen toxicity.
  • The King’s College Criteria identify two groups of patients that have a poor prognosis with acetaminophen induced liver failure (http://en.wikipedia.org/wiki/King’s_College_Criteria)
  • -J Pediatr 2009; 155:801.  Diagnostic evaluation in ALF  –wide variation.  Often not tested for AIH, wilson’s, HAV, HBV
  • -NEJM 2009; 361: 2105.  Changes in FDA labeling of analgesics.  ~30,000 hospitalizations /yr due to acetaminophen overdose in U.S.  –1/2 inadvertent overdose.  Maximum dose -650mg.
  • -Hepatology 2007; 46: 966.  AASLD public policy.  It is leading cause of acute liver failure in U.S –50% of cases with 30% mortality rate.  500 deaths annually.  10% of cases may occur in those receiving the proper doses. In single year, acetaminophen causes more deaths than all the years of statins.
  • -JAMA 2006; 296: 87-93.  Prospective study of daily 4gm acetaminophen in healthy volunteers.  (stayed at research facility).  ALT >3 ULN in 38%.  Resolved over 6 days.
  • -Liver Transplantation 2006; 12: 682.
    -Hepatology 2005; 42: 1364-72.  74 pts died & 23 needed Tx during  6 yr period at 22 tertiary care centers.  48% of cases were unintentional overdoses.
  • -J Pediatr 2002; 140: 522.  Predictors of outcome p acetaminophen ingestion.