More from Aspen Webinar 2021. This blog entry has abbreviated/summarized several presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well. An excellent review from Dr. Sokol.
What’s New with IFALD Ronald Sokol
Biliary cirrhosis related to parenteral nutrition has been the major indication for small bowel transplantation/multi-visceral transplantation. IFALD presentations: Steatosis, biliary tract disease and cholestasis
Conjugated bilirubin >2.5 had RR 22.5 for mortality (prior to availability of intestinal transplantation)
Even after weaning off PN, studies have shown long-lasting fibrosis and steatosis in more than 40% of patients (>8 yrs off PN)
Intestinal microbiome is altered in patients with IFALD
Puder M et al. (Ann Surg 2009; 250: 395) showed that fish oil (at lower doses) was associated with improvement/resolution of parenteral nutrition associated cholestasis (PNAC)
Lipid reduction also is associated with cholestasis resolution
Caution with Fish oil (omegaven): 1. Does not prevent hepatic fibrosis progression 2. Reduction of lipid doses can have negative effects on brain growth
Lipid management has been crucial in reducing the number of children needing intestinal transplantation
Some of the slides:
IBAT Inhibitors Frederick Suchy
IBAT inhibitors block intestinal absorption of bile acids/disrupt enterohepatic circulation; this leads to augmented bile acid excretion in stools
IBAT inhibitors may reduce liver damage in the setting of cholestasis/accumulation of toxic bile acids
Potential diseases for IBAT inhibitors include Alagille syndrome and PFIC
Van Wessel et al (J Hepatol 2020; 73: 84-93) correlated survival with PFIC1/PFIC2 with bile acid levels and showed improvement in survival in those with surgical biliary diversion
Goals for IBAT inhibitor trials: improvement in pruritus, bile acids, reduced ALT, hepatic fibrosis, HCC and need for liver transplantation
Marixibat is available for use as an FDA approved breakthrough medication for Alagille and PFIC2 in pediatric patients older than 1 year
Odexibat is designated as an orphan drug for Alagille, PFIC, PBC, and biliary atresia
Safety appears good with IBAT inhibitors. Fat soluble vitamin monitoring is needed
Case report: Alejandro Velez Lopez
3 yo presented with fatigue and jaundice, 3 weeks after COVID-19 infection. She was not taking any medications. Labs: ALT 939, AST 1321, T bili 5.5, D bili 0.9, INR 2, Plts 174, Hgb 12.8, LDH 1297. remained positive for SARS-CoV2 by PCR. Acetaminophen -no exposure. Evaluation: LKM 1:1280. Neg ANA, NL Ferritin, NL sIL2r, Other viral studies negative, NL IgG. Developed encephalopathy with NH4 317, INR peaked at 2.8. Treated with steroids, rifaximin and lactulose. Liver biopsy showed sub-massive necrosis and fibrosis (indicative of autoimmune hepatitis, likely triggered or exacerbated by COVID-19). Patient responded to medical therapy and did not require liver transplantation.
Among FOLE recipients (n=189), 65% experienced cholestasis resolution vs 16% of SOLE recipients (n=73) (P < .0001).
The aspartate aminotransferase to platelet ratio index scores improved in FOLE recipients (1.235 vs 0.810 and 0.758, P < .02) but worsened in SOLE recipients (0.540 vs 2.564 and 2.098; P ≤ .0003)
Liver transplantation was reduced in FOLE vs SOLE (4% vs 12%; P = .0245).
My main criticisms of the study:
While the methods explain that FOLE received 1 gm/kg/d, compared with 3 gm/kg/d for SOLE, this was NOT reviewed in the discussion. This is quite important in terms of proving that one product is preferred over the other. With lipid toxicity, it would be expected that delivering 3 times as much would be more damaging on the liver.
The discussion has only a single sentence regarding the change in care between the eras of SOLE and FOLE: “Additional limitations include a relatively small sample size and changes in surgical, medical, and nutritional practice between the 2 eras that could not be controlled for this study.”
Also, the discussion omits the development of other FOLE alternatives (eg. SMOFlipid) which has been a very important advance in the management of patients with SBS.
The commentary by Samuel Kocoshis (J Pediatr 2021; 230: 11-12) provides a good deal of insight. The title and first paragraph provides some interesting historical context: (full text) “Even When the Would Is Healed, the Scar Remains” “The above maxim was coined by the Roman author Publilius Syrus when referring to wounds of most tissues or body parts.1 Because hepatic regeneration was recognized (as evidenced by the story of Prometheus’s liver being eaten daily by an eagle only to regenerate the next day) in Syrus’s time, his dictum was too far too simplistic when applied to the liver. One must delve more deeply into the mechanism of liver injury to ascertain just when hepatic scaring persists or when it disappears.”
My take: This study illustrates harm reduction with the change in lipid administration. The development of new lipid products has made a huge difference in the outcomes of children with short bowel syndrome.
Briefly noted: M Sorrell et al. JPGN 2017; 64: 783-88. In this small study with 13 infants (mean gestational age of 28 weeks) who had short bowel syndrome or severe dysmotility and direct bilirubin ≥4 mg/dL (mean 9.8 at enrollment), patients received a fish oil-based lipid emulsion (1 g/kg/d). They were compared with 119 GA-matched controls.
Overall, the authors found the fish oil supplement to be safe. All patients had resolution of cholestasis. They note the difficulty of proving effectiveness and performing studies in this population. “Neonatologists…find themselves faced with …a growing body of uncontrolled data that suggests benefits of an unapproved treatment…An attempt to perform a randomized controlled comparison of a plant-based lipid emulsion to FishLE in preventing PNALD in infants at risk was terminated early after an interim analysis revealed much lower than expected incidence of PNALD…[making] trials ethically problematic.”
My take: The data remain incomplete and make it difficult to use a therapy like Omegaven that is quite expensive (not covered) and not FDA approved. The availability of SMOFlipid is likely to result in less usage of plant-based soy products.
More data on the progress of treatment of short bowel syndrome (SBS) programs:
Avitzur J, et al. JPGN 2015; 61: 18-23
In this study, the researchers from Toronto and the Group for Improvement of Intestinal Function and Treatment (GIFT) retrospectively examine 84 patients over 3 time periods: 1999-2002, 2003-2005, and 2006-2009.
Across those time periods, the authors find fewer SBS patients that needed to be listed for transplantation despite similar baseline characteristics. In addition, many more patients in the late period were removed from the transplant waiting list due to clinical improvement.
Another important finding was a drop in mortality (15% vs >60%) and a shift from previous causes like liver failure and sepsis to death from other comorbid conditions.
“Since 2009, we have performed only 1 IT [intestinal transplant].” They note this is a worldwide trend with ~50% reduction in pediatric IT since 2008.
Even with ultrashort bowel (small bowel length <30 cm), there are reports that “50% of these patients achieved PN independence within 2 years.” As such, this is a declining indication for IT listing. In this study, ultrashort bowel was the reason for listing in 11% in the last period compared 21% in the first time period.
Why is this happening?
The authors credit the intestinal rehab program (IRP) for this impact along with specific management changes including new lipid emulsions/lipid minimization to reduce IFALD, use of ethanol locks to reduce bloodstream infections, and bowel reconstructive procedures (e.g. STEP).
Briefly noted: Merras-Salmio L, Pakarinen MP. JPGN 2015; 61: 24-9. This second retrospective study (n=48) from Finland reinforces the view of improvements in cholestasis and prognosis from 1988-2014. Similar strategies, as noted above, were implemented in SBS management protocols.
Bottomline: The outlook has improved for SBS. While this is good news, at the same time, there will be less pediatric gastroenterologists with extensive intestinal transplantation experience.
In Wyoming often there are stretches of nearly deserted highways
A recent study (J Pediatr 2014; 165: 59-64) identified seven liver-inclusive intestinal transplants who had received O3FAs. This retrospective review study took place between 2003-2012. These seven patients had received O3FAs for a mean of 62% of their total life span before transplant. While these patients almost all had resolution of cholestasis (mean total bilirubin 0.7 mg/dL at time of transplant), advanced fibrosis (stage 3 or 4) was noted on explant pathology. The histologic inflammatory scores were lower (P=.056) in comparison to O6FA group.
The authors make several important points:
The “results provide additional evidence that the improvement in hyperbilirubinemia following O3FA substitution therapy does not consistently produce histologic recovery of the liver.”
This study does not address whether comparable improvements could have been obtained from lipid restriction among the O6FA group.
Only 1 of 20 studies of O3FA lipid emulsion in PNALD includes hepatic histopathology as an outcome measure.
This is not the first study that indicates that liver fibrosis may persist and progress on O3FA therapy (J Pediatr 2010; 156: 327-31, J Pediatr Surg 2010; 45: 95-9, JPGN 2013; 56: 364-9).
Bottomline: Continued investigation of O3FA emulsions in PNALD is needed and assessing liver histology may be needed prior to intestinal transplantation.
A recent study indicates that patient’s placed on omega-3 lipid emulsions (eg. Omegaven) may be at risk for bleeding due to platelet dysfunction (J Pediatr 2014; 164: 652-4).
While omega-3 lipid emulsions have received a lot of attention due to improvements in intestinal failure associated liver disease (IFALD) (see previous links to prior posts below), the amount of data supporting their usage and potential advantages compared with standard lipids at similar dosing remains limited.
This case report describes a 9-month old who developed life-threatening hemorrhage following a standard central line placement. Due to difficulty stopping the bleeding, the patient’s omegaven was discontinued. Standard workup for bleeding disorders were negative. Subsequently, the authors investigated clot formation and platelet function in a neonatal animal model.
Key Result: Piglets treated with omegaven had a doubling of time to clot formation and marked platelet agonist inhibition.
The discussion notes that “there is an acknowledged risk of high dose O3FA lipids [omegaven] increasing bleeding time because of competitive inhibition of AA [arachidonic acid] production, hence decreased TxA2 [thromboxane A2]. In addition, platelet-derived growth factor-like protein and endothelial platelet activation factor are decreased.”
Take home points (from the authors):
“the case report and piglet studies together demonstrate that there is potential for a significant antiplatelet effect and inhibition of the coagulation cascade with O3FA therapy…”
“We would suggest discontinuation of Omegaven therapy 72 hours preoperatively in high-risk cases where bleeding may be difficult to directly control.”
“Institutionally, we have abandoned the sole use of Omegaven therapy.”
According to a systematic review of the literature regarding ω-3 (n-3FA) fatty acid lipid emulsions, there is a “lack of sufficient high-quality data to support the use of parenteral n-3FA lipid emulsions in children” (JPEN 2013; 37: 44-55). Thanks to Kipp Ellsworth for this reference.
The authors of this study researched 4 databases up to March 2011 and extracted relevant studies. Five randomized controlled trials and 3 high-quality prospective cohort studies were included. The strength of evidence was “consistently low or very low across all lipid emulsion comparisons and outcomes.”
Few studies examined important outcomes like length of hospital stay or intensive care stay.
There was lack of data on growth, cognitive development or potential long-term effects/harms.
All of the studies in children varied considerably with regard to the dosing regimens, duration of administration, and duration of followup.
The studies were small with sample sizes ranging from 28-91 patients.
The 5 RCTs had unclear risk of bias due to inadequate blinding of participants and study personnel.
All of the RCTs were funded by the manufacturer.
While some biochemical outcomes improved, no difference in mortality has been identified. A biochemical response is a poor measure of effectiveness. In fact, several studies have shown deterioration in liver histology and fibrosis despite improved biochemical measures in infants on Omegaven.
For Omegaven (fish oil) treatment, all studies used a historical control group. In these studies, typically the Omegaven dose was half the dose of Intralipid used in the control group.
This article (in its Table 1) identifies the constituents in the commercial available lipid products which include Intralipid, Clinoleic, Liposyn II, Omegaven, SMOFLipid, and Lipoplus. Intralipid which is widely used is devoid of substantial arachidonic acid (ARA) and docosahexaenoic adic (DHA). This is particularly important in premature infants as noted in recent blogs:
Intravenous lipids may cause parenteral nutrition associated cholestasis (PNAC), parenteral nutrition associated liver disease (PNALD), or intestinal failure associated cholestasis (IFAC) (J Pediatr 2012; 160: 421-7 & editorial 361-2). PNAC refers to cholestasis due to parenteral nutrition and PNALD refers to PNAC that has progressed to liver dysfunction or permanent liver injury.
In a previous blog (Four advances for intestinal failure), one of the advances for intestinal failure that was noted was the reduction of lipid infusions with parenteral nutrition which reduces IFAC. This study adds additional information to this area. In this prospective study, 31 patients were enrolled in a reduced IV fat emulsion group and compared with a matched historical control group. The reduced fat group received 1gm/kg of a standard soybean-based lipid emulsion (liposyn 20%) twice weekly. Patients were eligible if they received PN for >2 weeks and had a direct bilirubin >2.5 mg/dL.
Total bilirubins dropped 0.73 mg/dL each week in the reduced fat group; in the control group, the bilirubin increased 0.29 mg/dL each week
Growth was similar in both groups
Essential fatty acid deficiency (biochemical not clinical features) was identified in 13 of 31 infants among the restricted IV fat emulsion group.
Essential fatty acid deficiency was defined as having a triene: tetraene ratio >0.05 (mild), >0.2 (moderate) or >0.4 (severe).
Historical control group & small study population
Fat-restricted group received enteral antibiotics which may have helped reduce cholestasis
Majority of patients with relatively short duration of TPN: 18 of 31 for less than one month
The reasons why lipids may contribute to PNAC/PNALD/IFAC include the presence of phytosterols. This in turn may damage hepatocytes via the farnesoid X receptor. One other aspect of the study was that the fat-restricted cohort had a higher mortality. This was thought to be related to the cohort being sicker rather than to any nutritional effect. Specific causes of death included respiratory failure in a patient with an abdominal wall defect, chylothorax/sepsis in a patient with a congenital diaphragmatic hernia, and cardiopulmonary failure in a patient with pulmonary hypoplasia.
The article does throw into question whether the use of a fish oil lipid preparation is needed to improve cholestasis. In studies supporting fish oil preparations, a confounder was that the total lipid administered was reduced to 1 gm/kg/day in comparison to soybean lipids which were administered at 2-3 gm/kg/day. This study suggests that reducing the total amount of lipid infusion is the more important factor.
The accompanying editorial makes a couple of useful points:
Increasing enteral feeds (>50%) is as effective as using less intravenous lipids
Use of standard lipids at 1gm/kg/day decreased IFAC from 15% to 4% in their intestinal failure patient population
Drastic reductions in lipids lead to essential fatty acid deficiency and should be avoided.
Use of Omegaven has not been shown to prevent liver fibrosis even with resolution of cholestasis; similarly, these studies do not inform fully on the long-term liver effects of reducing standard lipids
Neurologic followup will be important
Explains “Morton’s fork.” John Morton was a 16th century Archbishop who wanted to increase taxes on people who were living lavishly. In addition, he wanted to increase taxes on those living modestly (must be hiding wealth).
-NEJM 2010; 362: 181. Letter to editor describes use of fish oil in (n=125) Boston pediatric patients.
-JPGN 2009; 48: 209. n=12. SBS. 9/12 improved with Omegaven. 3 had transplant (L-ITx). No controls.
-Pediatrics 2008; 121: e678-86. n=18. Use of fish oil improved cholestasis compared to historical controls.
-Pediatrics 2006; 118: e197-e201. Reversal of TPN-AC c IV omega-3 fatty acids (fish oil-derived) instead of intralipids