Category Archives: Pediatric Gastroenterology Liver Disease

Extended data with entecavir & annotated HBV management references

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Long-term data for entecavir continue to look good (Clin Gastroenterol Hepatol 2012; 10: 1047-1050).

With this study, the authors performed a post hoc analysis of 94 Asian patients with hepatitis B e antigen-positve (HBeAg+) nucleus(t)ice analogue-naive patients who received 5 years of entecavir therapy.  By five years, 66 patients remained in the study; of the other 28: 11 withdrew consent, 4 completed treatment, 5 died, 2 were lost to followup, 2 had minimal virologic response, and 4 had other reasons.

Results:

  • 63 of 66 (95%) patients who completed 5 years of therapy had HBV DNA < 300 copies/mL
  • 50 of 66 (76%) had normalized levels of alanine aminotransferase
  • 26 of 65 (40%) had HBeAg loss
  • 12 of 65 (18%) had HBeAg seroconversion
  • No resistance to entecavir was detected

Related blog entries:

References on Hepatitis B Management:

  • –Chronic Hepatitis B: Update_2009 AASLD Practice Guidelines
  • -Clin Gastroenterol Hepatol 2011; 9: 85. Mgt recommendations.
  • -Hepatology 2010; 52: 2192. Consensus guidelines suggest that IFN is treatment of choice in pediatric pts (<16yrs) due to resistance among nucleosides and lack of pediatric studies with these agents along with PEG-IFN. Does not recommend Rx for immune tolerant (NL ALT, HBeAg+, HBV >20K), inactive dz (NL ALT, HBeAg-Neg, HBV <2K), mild disease. Reactivation (HBeAg-Neg, HBV>2K IU/mL & +ALT1.5ULN or >60) & Immune active (+ALT1.5ULN or >60, HBeAg+, HBV >20K) can be treated if mod-severe dz.
  • -JPGN 2009; 48: 399-404. For children, IF +HBeAg/HBV DNA> 20,000 IU/mL & ALT>2 x ULN, Rx post 3months (sooner if decompensating). IF +HBeAg/HBV DNA> 20,000 IU/mL & ALT<2 x ULN or if inactive replication, then monitor. Consider: Follow yearly U/S, q6mo AFP.  IF HBV DNA <20K U/mL & NL ALT: no Rx, monitor q6-12mo. IF HBV DNA >20K U/mL & NL ALT, low rate of HBeAg conversion, young pts often immunotolerant, consider biopsy, esp if >35yrs.  IF HBV DNA >20K U/mL & incr ALT, then Rx options entecavir, tenofovir, PEG interferon alfa-2a preferred.
  • Hepatology 2009; 49: May 2009 supplement -Entirely on management of HBV: S1-S199. NIH Consensus conference. S8: “Reasonable to monitor this group ((younger than 40/HBeAg+) without therapy unless evidence of progressive liver disease is found” S10 Table 1 -Criteria for determining Rx. Generally not indicated: immune-tolerant phase (High HBV DNA but normal ALT or little activity on Bx).S119: “almost all of the oral agents are superior to interferon-based therapy in achieving other clinical endpoints…and in achieving biochemical and histological improvement…in addition, with longer use, oral agents can equal and exceed the level of pegIFN-associated HBeAg & HBsAg serologic responses w/o the need for injections, side effects…”
  • -Hepatology 2009; 49: 699. German Rx guidelines: IF HBV DNA+ & Cirrhosis –>Rx. IF HBV DNA >10 to 4th and any of the following: ALT >2X, F2 + inflammation, Risk HCC/extrahep dz—>Rx. If none of these reeval q6-12mo

Additional entecavir/tenofovir references:

  • -Gastroenterol 2011; 141: 1212. Entecavir effective as monotherapy post OLT.
  • -Hepatology 2010; 53: 763. No resistance with tenofovir over 2yrs. n=641 (HBe+ & HBe-neg)
  • -Gastroenterol 2011; 140: 132. n=365. Excellent efficacy of tenofovir over 3 yr Rx for HBV. 87% of HBeAg-neg with undetectable HBV & 74% of HBeAg-pos. 8% of HBeAg-pos lost HBsAg & 34% lost HBeAg.
  • -Hepatology 2009; 51: 73. n=131. Tenofovir Rx.
  • -Clin Gastroenterol Hepatol 2010; 9: 274. Use of entecavir (long term) reverses fibrosis in HBV
  • -Hepatology 2010; 52: 886. Long term entecavir Rx (>6yrs) with good efficacy & improved histology (96%), n=69.
  • -Hepatology 2009; 49: 1503. Long term entecavir Rx with LOW resistance. n=608 @ yr1, 108 @ yr5. Resistance ~1%
  • -Hepatology 2009; 50: 1064. Entecavir less effective in pts with combined LAM/ADV resistance.
  • -Hepatology 2008; 48: 99. Entecavir for lamivudine-refractory HBV thru 96 weeks. n=141 entecavir, n=145 lam. Entecavir fairly effective (81% had NL Alt, 10% HBeAg seroconversion) 6/77 in 2nd yr developed resistance much higher than those in studies who never rec’d lamivudine
  • -NEJM 2007; 356: 2614. Use entecavir with caution in pts coinfected w HIV -may select for resistant organisms in those not on fully sppressive antiretroviral regimens.
  • -NEJM 2006; 354: 1001, 1011, 1074. Hepatitis B patients: At 48 weeks, Entecavir-Rx’d HBeAg+ had 72% histologic response, 67% c undetectable HBV DNA, and 68% normalized ALT (n=314/314 entecavir/lamivudine pts). At 48 weeeks among HBeAG-neg, 90% in entecavir group (n=296 vs. 287 lamivudine pts) w/o detectable HBV DNA, 78% c Nl ALT, 70% c histologic improvement. Entecavir has caused cancer in mice.
  • -Hepatology 2006; 44: 1656. Entecavir had highly potent efficacy in reducing HBV DNA levels to <300 copies/mL. Study of 673 Rx’d pts. In HBeAg+, 69% were HBV DNA-neg at 48 weeks, & 82% at 96 weeks; in HBeAg-neg, 93% at 48 weeks & 96% at 96 weeks were HBV DNA neg. Low level of resistance due potent HBV DNA levels.

Portopulmonary Hypertension

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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

Sirolimus and transplant mortality

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A surprise to me was a recent study which identified sirolimus as a risk factor for increased mortality and graft loss in HCV-positive liver transplant patients (Liver Transpl 2012; 18: 1029-36, commentary 1003-1004).

Sirolimus mechanism of action: inhibits mammalian target of rapamycin (mTOR) which is a phosphoinositide 3-kinase which affects cell proliferation, angiogenesis, and immune function.  For transplant patients, sirolimus blocks interleukin-2-induced stimulation of T lymphocytes.

Black box warnings for sirolimus: FDA warns that sirolimus can increase risk of hepatic artery thrombosis, graft loss, and death with de novo sirolimus-based treatment.

What’s different about HCV transplants? HCV reinfection occurs immediately during liver transplantation and “unlike all other indications, graft survival and patient survival have not improved” (between 1991-2001).  HCV transplant survival continues to be 10-15% lower than non-HCV transplant survival.  Immunosuppression allows more rapid progression of HCV; this allows ~20% of recipients to develop cirrhosis within 5 years of transplantation.

The authors of the study analyzed 26,414 patients (12,589 with hepatitis C virus) from the Scientific Registry of Transplant Recipients (SRTR) database; all recipients were >18 years.  Among this database, 1685 liver transplant recipients received sirolimus; in the majority, it was administered along with a calcineurin inhibitor.  A multivariate analysis of patient mortality showed the following were risk factors for increased mortality:

  • recipient age
  • donor age
  • hepatocellular carcinoma
  • diabetes
  • creatinine

Tacrolimus-based immunosuppression was associated with superior survival. Whereas, the use of sirolimus was associated with increased mortality in patients with HCV, even when adjusting for confounding variables (eg. renal function, and cancer).  In patients who received sirolimus at baseline, the adjusted HR for mortality at 3 years was 1.29 (p=0.0053).  In non-HCV patients, the adjusted HR for the sirolimus group was 1.09  (p=0.40).  Also, duration of exposure to sirolimus was directly correlated with worse outcomes.  Why?

This is not clear.  It is recognized that the study has several limitations.  Due to the nature of the SRTR database, there is not adequate information on how sirolimus may have affected viral load, histologic progression or causes of death.  Despite attempts to control for risk factors, it is possible that the sirolimus group did have higher disease severity.  Nevertheless, sirolimus effects on multiple cellular functions may have deleterious consequences in certain subsets of patients.

Hepatitis A vaccine immunity –will it last?

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In a previous post (HAV vaccination: how long will it take?), it was noted that U.S. HAV immunization rates are poor but much better in states that have employed a strategy of implementing universal vaccination for a longer period.  Another article provides reassurance that once patients are vaccinated that the immunity is quite durable (Hepatology 2012; 56: 516-22).

197 infants and children were followed after HAV immunization; these patients were divided into three groups; two dose immunization at 6 & 12 months (group 1), at 12 & 18 months (group 2), and at 15 & 21 months(group 3).  Anti-HAV serology was followed sequentially. At 10 years, almost all children retained seroprotection (>10 mIU/mL) levels, >95% of group 2 & 3.  In group 1,  7% of infants born to anti-HAV negative mothers and 11% of infants born to anti-HAV positive mothers did not have protective antibody levels.

Conclusion: Seropositivity for HAV persists for at least 10 years after vaccination with two-dose regimen when administered to children 12 months of age and older.

Something to think about (unrelated to blog post):

A Zen master was once asked, “What is the key to happiness?”

He answered, “Good judgment.”

“How do I gain good judgment?” he was questioned.

“Experience,” was the reply.

“How then do I get experience?” the student further probed.

“Bad judgment,” were his final words.

(quoted previously in Pediatrics and from the following link QUOTATIONS AND PASSAGES ON EXPERIENCE)

TPN cycling

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A randomized prospective study of early parenteral nutrition cycling was not helpful in reducing parenteral nutrition associated cholestasis (PNAC): J Pediatr 2012; 161: 229-33.

This study enrolled preterm infants <1250 g in the first five postnatal days to either cycled (n=34) or continuous parenteral nutrition (n=36).  Cholestasis was defined as direct bilirubin >2 mg/dL. The study indicated that intralipid 20% was administered in all patients over 18 hours; the exact amount is not clear, though in the cycled group, patients received 3 g/kg/day on postnatal day 3.9 ± 2.6.  All patients received dextrose over 24 hours; only the amino acid (TrophAmine) infusion varied: 20 hours compared with 24 hours.

  • PNAC in each group was nearly identical, 32% vs 31% as were bilirubin and transaminase values.
  • While the study was randomized, the cycled group did have more frequent late-onset sepsis 22 (65%) compared with 14 (39%) which reached statistical significance.
  • In addition, a trend towards more frequent non-surgical NEC in cyclical group was noted as well: 6 (18%) compared with 3 (8%).
  • PNAC was associated with days until full enteral nutrition/duration of parenteral nutrition and bronchopulmonary dysplasia.

The higher incidence of late-onset sepsis could have occurred randomly and affected the results; alternatively, the higher rate could reflect an increased risk of sepsis due to doubling the frequency of central line access.

This study was  only powered to detect a 25% difference between the groups; the authors estimate that a study with 290 patients would be needed in each group to identify a reduction of 10% in the incidence of PNAC.  As such, this study leaves open the possibility that cycled parenteral nutrition may be helpful in a smaller percentage, particularly if efforts are made to eliminate central line infections.  More promising efforts to minimized PNAC are noted in previous blog entries:

PNAC, PNALD, and IFAC

Optimizing lipids to minimize cholestasis

More on PNAC

Four advances for intestinal failure

Understanding IL28B

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Interleukin-28B (IL28B) has been a phenomenal discovery in the field of hepatitis C (HCV); yet, with the emergence of direct-acting antiviral (DAA) agents, its importance has been overshadowed.  While the long-term significance of IL28B is unclear, for now, it has significant clinical utility.  Three reviews/commentaries help elucidate its role:

▪                Hepatology 2012; 56: 361-66. IL 28B Genetics and Biology

▪                Hepatology 2012; 56: 367-372 Clinical Utility of IL28B

▪                Hepatology 2012; 56:  373-380 Relevance of IL28B in age of DAAs

Key points from these references:

African-Americans are less likely to respond to treatment with pegylated interferon (PEGIFN) (and ribavirin [RBV]) in large part due to a low frequency of favorable alleles (C/C genotype) to IL28B.

Predictors of response to treatment with PEGIFN/RBV:

▪                CC IL28B genotype: OR 5.9 (compared to non-CC genotype)

▪                HCV RNA level ≤600,000 IU/mL: OR 3.1 (compared to >600,000 IU/mL)

▪                Degree of fibrosis, metavir F0-2: OR 2.7 (compared with F3-F4)

▪                Rapid virological response: OR 9.1 (compared with non-RVR non CC genotype)

Overall CC genotype is associated with double the sustained virological response (SVR).

Vitamin D also plays an important role in innate immunity and deficiency is associated with lower SVR.

Algorithm for use of IL28B (applicable to patients ≥18 years):

▪                Consider obtaining IL28B in all genotype 1 patients:  

▪                If CC genotype and does not have risk factors for poor response (including cirrhosis, high viral load), then likely to treat with PEGIFN/RBV and monitor for RVR.  In patients without RVR, addition of DAA would be reasonable.

▪                If risk factors for poor response or if non-CC genotype (C/T or T/T), then consider use of DAA at onset of therapy

DAAs are expensive.  Boceprevir (BOC) costs $26,000 for 24 weeks & $48,000 for 44 weeks.  Telaprevir (TVR) costs $49,000 for 12 weeks.  These costs are in addition to costs for PEGIFN/RBV which is approximately $30,000.  The cost of testing IL28B status is approximately $300.

In patients with CC IL28B genotype, the main advantage of DAAs may be to shorten treatment course by increasing the likelihood of RVR; though with TVR, the SVR was improved even among CC genotype patients in the “ADVANCE” trial (90% compared with 64%).  In non-CC IL28B genotype, TVR or BOC is associated with > 2-fold increase in SVR.  The specific response rates for both TVR and BOC are available in these references.

Related blog entries

Pediatric HCV Guidelines

Increased ferritin predicts poor response in Hepatitis C

Unknown unknowns for Hepatitis C

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Effects of pegylated interferon on growth

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Besides examining the effectiveness of pegylated interferon for hepatitis C virus (HCV) in children, the PEDS-C (Pediatric Study of Hepatitis C) trial data has been studied to determine the effects of pegylated interferon (PEG) on growth and body composition (Hepatology 2012; 56: 523-31).

In this study of 114 children who were treated with PEG along with ribavirin (RBV), anthropometric measurements, dual-energy X-ray absorptiometry, dietary intakes, and activity assessments were performed.  Of the initial 114 children (5-18 years), 107 received treatment for more than 24 weeks: 14 for 24 weeks, 82 for 48 weeks, and 11 for 72 weeks.

In the group treated for 48 weeks, 29 (33%) had more than a 0.5 unit decrement in height-for-age score (HAZ).  Based on figure 2 in the study, most of the HAZ decrement at 48 weeks and resolved at 144 weeks (time after treatment initiation).  In contrast, weight-for-age and BMI scores returned to baseline after stopping HCV therapy.  The authors note that while most growth parameters generally were “reversible with cessation of therapy…HAZ scores had not returned to baseline after 2 years of observation in many.”

Another observation from the study was that weight and height decreased in tandem.  In contrast to sequential change, this type of change indicates that other mechanisms besides poor intake are likely affecting linear growth.  These HAZ effects were noted in adolescents; there was no difference in HAZ scores in preadolescent patients.

The potential effects on growth may influence the timing of therapy.  At the same time, as new HCV treatments are studied in pediatric patients, the effects of interferon may become a moot point.

Related blog entries

Pediatric HCV Guidelines

Understanding IL28B

Increased ferritin predicts poor response in Hepatitis C

Unknown unknowns for Hepatitis C

Alagille and liver transplantation

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Alagille syndrome (ALGS) is an autosomal dominant disorder which affects 1 in 30,000.  More information is available regarding the outcome of ALGS patients who have undergone liver transplantation (Liver Transpl 2012; 18: 940-48).

Using the SPLIT (studies of pediatric liver transplantation) database, the outcome of 91 ALGS patients was compared with 236 age-matched biliary atresia (BA) patients in a retrospective review (1995-2009).

  • 1-year survival was 87% for ALGS and 96% for BA (p=0.002).  Most of the ALGS deaths occurred in the initial 30 days.  No pretransplant factors could be identified which were associated with mortality.
  • Renal insufficiency worsened after liver transplantation in ALGS patients with 22% having glomerular filtration rate <90 mL/minute/1.73 meter squared; 8% of BA had similar renal insufficiency.
  • ALGS patients were more likely to receive special education: 50% compared to 30% for BA patients.
  • Increased mortality risk was not apparent after the 1st year following transplantation.  At 60 months post-transplantation, survival was 86% for ALGS group and 94.4% for BA group.
  • One other interesting finding was that 21% of ALGS group had undergone Kasai procedure prior to liver transplantation which may have a detrimental effect on liver outcome.

Since ALGS is a systemic disorder, it is not surprising that outcomes are inferior.  These patients frequently have a wide range of heart disease, renal dysfunction, and vascular disorders, including risk for intracranial hemorrhage.  In this series, intracranial hemorrhage occurred in one patient in each group.  It is noted that chidren with ALGS did have a vascular complication in 21% in the first 30 days after transplantation.

Information on Alagille:

There is family-oriented information on the ChiLDREN website.
http://childrennetwork.org/

There is also an Alagille Syndrome Alliance website.
http://www.alagille.org/

Additional Alagille references:

  • -JPGN 2010; 50: 11. Alagille Syndrome and Liver Transplantation
  • -JPGN 2011; 52: 84. King’s College experience.n=117.  HIDA scan w/o excretion in 60%.
  • -JPGN 2010;  51: 319.  Kasai procedure likely worsens outcome. N=19 out of 430 cohort.
  • -JPGN 2010; 50: 526.  TB >6.5, DB >4.5 & cholesterol >520 indicate likely severe liver dz in infancy & should be referred.
  • -JPGN 2010; 51:66.  Frequent bone fractures (esp LE), with peak age ~5yrs.
  • -Gastorenterol Clin N Am; 2003; 32: 857-75.  “Heritable disorders of the bile ducts” Kamath BM, Piccoli DA
  • -JPGN 2008; 47: 623. Urso may help c milder dz. n=42.
  • -JPGN 2005; 41: 676.  Increased risk of HCC.
  • -NASPGHAN 2003:  Can place peg-like tube in gallbladder for biliary diversion (done at CHOP)
  • -Pediatrics 2003; 111: 167-70.  Increased bleeding episodes, 38 of 174pts had bleeding complication; lethal in 4 pts
  • -Hepatology 2002; 35: 1501-6.  Review of partial biliary diversion for Alagille.
  • NASPGHAN 2009, Postgraduate course, pg 51.  95% c JAG1mutation identifiable with commercial lab (others c NOTCH2 mutation can be identified in research lab)

Fat soluble vitamin deficiency -sometimes the rule rather than the exception

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While it is well-known that cholestasis predisposes individuals to develop fat-soluble vitamin (FSV) deficiencies, the exact frequency is not clear.

A recent prospective multi center study of infants with biliary atresia (BA) indicates that FSV deficiency is quite frequent –thanks to Kipp Ellsworth for forwarding this article (DOI: 10.1542/peds.2011-1423; http://pediatrics.aappublications.org/content/early/2012/08/08/peds.2011-1423).  “Infants with BA are at risk for malabsorption of dietary lipid and fat-soluble vitamins (FSVs) due to insufficient intraluminal bile acid concentrations.”

To determine the frequency of FSV deficiencies, this study examined 92 infants with BA who were enrolled in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE).  This study was conducted by the Biliary Atresia Research Consortium (BARC) between 2005-2008.

All infants were treated with a standardized dose of a liquid multiple FSV/d-α tocopheryl polyethylene glycol-1000 succinate (TPGS; a micelle forming water-soluble form of vitamin E).  Infants received initially ADEKs; later in the study, ∼32 months after start, participants were changed to AquADEKs due to a manufacturer’s change.  In addition, all infants received supplemental vitamin K, initially 2.5 mg three times per week.  As noted in supplement to article, the two study multivitamins have particularly low amounts of vitamin D (800 units) and vitamin E (80-100 units) compared to frequent dosing in clinical practice for severe cholestasis (see below).

TABLE 1 from study: Target FSV Levels and Replacement Regimens

  • Vitamin A (retinol)

Target:  19–77 mg/dL retinol:RBP molar ratio >0.8

Supplement strategy:  Increments of 5000 IU (up to 25–50 000 IU/d) orally or monthly intramuscular administration of 50 000 IU

  • D (25-hydroxy vitamin D)

Target: 15–45 ng/mL

Supplement: Increments of 1200 to 8000 IU orally daily of cholecalciferol or ergocalciferol; alternatively calcitriol at 0.05 to 0.20 mg/kg per day

  • E (α tocopherol) 

Target: 3.8–20.3 mg/mL & vitamin E:total serum lipids ratio >0.6 mg/g

Supplement: Increments of 25 IU/kg of TPGS orally daily (to 100 IU/kg per d)

  • K (phytonadione)

Target: INR ≤1.2

Supplementation Strategy:

  • <1.2-1.5  INR:  2.5 mg vitamin K orally daily
  • 1.5-1.8  INR: 1.8  2.0–5.0 mg vitamin K intramuscular and 2.5 mg vitamin K orally daily
  • >1.8 INR:  2.0–5.0 mg vitamin K intramuscular and 5.0 mg vitamin K orally daily

Results: FSV was common in infants with total bilirubin (TB) ≥2 mg/dL. At three months post HPE, only 3 infants with this degree of cholestasis were sufficient for all four vitamins.; at 6 months post HPE, all 24 infants with TB ≥2 mg/dL had at least one FSV deficiency: “100%, 79%, 50%, and 46%, respectively, for vitamins A, D, E, and K .”   Also, the incidence of vitamin D deficiency would be higher if the authors had chosen a higher target.

Take-home points:

  • FSV deficiencies are common particularly in patients with TB > 2mg/dL; thus careful monitoring is worthwhile
  • There is no current multivitamin that is adequate.  A better strategy is to individualize the dosing for each vitamin and consider injection (except for vitamin E) if needed

Initial individualized dosing of FSV supplementation in clinical practice for severe cholestasis (prior to deficiencies):

Vitamin A: start with ~5000 units daily.

Vitamin D: See previous posts for more information on dosing.  Two options include: Drisdol® (8000 IU/ml) 0.125ml/kg/day (=1000 IU/kg/day) and Bio-D-Mulsion Forte® http://www.bioticsresearch.com/node/1570 -each drop = 2,000 IU (also inexpensive)

Vitamin E (Liqui-E®/Nutr-E sol®26.6 IU/ml) 1ml/kg/day
with tocopherol polyethylene glycol succinate.  Alternative is AquaE®(Yasoo -www.yasooproducts.com/aqua-e/).

Vitamin K (phytonadione) 2.5mg QOD

Related posts:

Diagnosing biliary atresia earlier

Common to be “D-ficient”

Outcomes of Biliary Atresia

MicroRNAs and biliary atresia

Bleeding due to vitamin K deficiency

Optimizing lipids to minimize cholestasis

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As discussed in previous blog entries (PNAC, PNALD, and IFAC, More on PNAC, Four advances for intestinal failure), the right amount of lipid and the type of lipid both can contribute to parenteral nutrition associated cholestasis (PNAC).  More information about SMOFlipid which is a complex mixed-type lipid emulsion derived from soybean, coconut, olive, and fish oils is available (JPGN 2012; 54: 797-802).  SMOF contains 30% soybean oil, 30% MCT, 25% monounsaturated fatty acids, and 15% fish oil.

This study had a retrospective cohort comparison design & examined serum bilirubin over 6 months in children with PN-associated cholestasis (PNAC).  In one cohort, 8 patients received the SMOFlipid and the other 9 patients continued on Intralipid (IL).

The SMOF cohort was receiving 81% of caloric needs as PN at entry whereas the IL cohort was receiving 92%.  Six months later, SMOF cohort was receiving 68% of caloric needs as PN compared with 50% for IL cohort.  Nevertheless, the SMOF group had improved cholestasis with a median bilirubin drop of 99 μmol/L compared with an increase of 79 μmol/L among IL patients.  Overall, 5 of 8 children in the SMOF group had resolution of jaundice compared with 2 of 9 in the IL group.

While the authors state that SMOF may have important properties to prevent PNALD, the study has limited ability to draw any firm conclusions.

The authors state that no other treatment innovations were introduced; however, the authors overlook the large discrepancy in lipid volume administered.  The IL group was receiving much more lipid both before and during study.  Prior to entry of study, the IL group was receiving about 3.1 g/kg/day whereas the SMOF group about 2 g/kg/day; the SMOF group continued initially at the same lipid dosing with the new formulation.  This is one of the problems with historical controls.  While the authors might believe that the cholestasis improved because of the lipid content, the key factor may in fact be the amount of lipid given.

In the same issue (JPGN 2012; 54: 803-11), specific plant sterols (PS) were elevated among neonates with intestinal failure-associated liver disease (IFALD).  This study looked at 28 neonates and 11 children from Finland who required PN for more than 28 days.  Specific markedly-elevated PS included stigmasterol, sitosterol, avenasterol and campesterol (Table 4 in study).  Some of these PS in the neonates were more than 20-fold higher than healthy controls.