SH Ibrahim et al. Hepatology 2020; 71: 1474-85. Thorough review of liver diseases in the perinatal period and relationship of the maternal-infant interactions. Liver diseases discussed include GALD which has “strikingly normal or near normal transaminases” despite liver failure (most common etiology). Treatment for GALD includes IVIG (1 g/kg) along with subsequent double-volume exchange transfusion. The review covers maternally-transmitted viral infections, fatty liver disease, and acute fatty liver disease of pregnancy (AFLP); AFLP is most commonly caused by LCHAD but can be caused by other defects in fatty acid oxidation.
RT Khalaf, RJ Sokol. Hepatology 2020; 71: 1486-98. This review focuses on intestinal failure-associated liver disease (IFALD). The review provides an in-depth discussion of intravenous lipid emulsions and other factors implicated in the pathogenesis.
- Risk factors: bacterial overgrowth, central line infections, recurrent sepsis, prematurity, parenteral nutrition composition, and micronutrient imbalances
- Protective factors: early enteral nutrition, cycled parenteral nutrition, glucagon-like peptide 2, preservation of ileocecal valve, small bowel lengthening when appropriate
- While the authors acknowledge that lipid minimization often improves cholestasis, they advise caution due to concern for both essential fatty acid deficiency and detrimental effects on brain growth.
- Prevention of central line infections with use of ethanol locks is important and effectively reduces the rate by more than 80% (though currently costs of ethanol locks have skyrocketed: FDA Safety Initiative Complicit in Ethanol Costing $30,000 for 1 oz)
- The authors note that long-term survival from intestinal transplantation is only 40% at 10 years indicating benefit of ongoing parenteral nutrition management if feasible.
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PL Valentino et al. JPGN 2020; 70: 547-54. This article discusses potential management of Wilson disease diagnosed in infancy based on ATP7B genetic testing. Very little evidence presented. Suggests starting Zinc therapy at an early age and monitoring for copper deficiency along with efficacy. More precise recommendations regarding urine copper goals for children would be helpful as well.
Large (n=112, median age 38 years) prospective observational study of Acute Hepatic Porphyria. L Gouya et al. Hepatology 2020; 71: 1546-58. Key findings from EXPLORE group:
- Chronic symptoms were noted in 65%; 46% had daily symptoms. Symptoms including body pains, trouble sleeping/tiredness, anxiety, GI symptoms (eg. nausea) and weakness.
- During the 2-year study period, 88% experienced a total of 483 attacks; 77% of these attacks required treatment at a health care facility or hemin administration
- Median annualized attack rate was 2.0
- UrineDelta-aminolevulinic acid (ALA) and porphobilinogen (PBG) compared with upper limit of normal at baseline and increased further during attacks.
- At baseline, 16% had elevations of liver aminotransferases
- Related reference: M Balwani et al. Hepatology 2017; 66: 1314-22. Acute Hepatic Porphyrias -Review. Current recommendations include gene sequencing to confirm all biochemical cases. Biochemical tests are spot urine testing of porphobilinogen (PBG), 5-aminolevulinic acid (ALA), and porphyrins. A normal urine PBG in symptomatic patients “excludes the three most common acute hepatic porphyrias.” For those with abnormal studies, this reference is a handy.
Automated ascites pump. F Wong et al. Liver Transplantation 2020; 26: 651-61. In this study with 30 patients, interventional radiology placement of an “alfapump” helped manage refractory ascites in cirrhosis.
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
A recent study (C Belza et al. JPEN 2019; https://doi.org/10.1002/jpen.1692) showed that SMOFlipid reduced the frequency of cholestasis in intestinal failure patients. Thanks to Kipp Ellsworth for reference.
An Observational Study of Smoflipid vs Intralipid on the Evolution of Intestinal Failure–Associated Liver Disease in Infants With Intestinal Failure. From Abstract:
This was a retrospective cohort study of infants with IF with a minimum follow‐up of 12 months in 2008–2016. Patients were stratified into 2 groups: group 1 received SMOFlipid; group 2 was a historical cohort who received Intralipid. The primary outcome was liver function evaluated using conjugated bilirubin (CB) levels…
Thirty‐seven patients were evaluated (17 = SMOFlipid, 20 = Intralipid). SMOFlipid patients were less likely to reach CB of 34 (24% vs 55%, P = 0.05), 50 µmol/L (11.8% vs 45%; P = 0.028), and did not require Omegaven (0% vs 30%; P = 0.014). CB level at 3 months after initiation of parenteral nutrition (PN) was lower in patients receiving SMOFlipid (0 vs 36 µmol/L; P = 0.01). Weight z‐scores were improved for patients receiving SMOFlipid at 3 months (−0.932 vs −2.092; P = 0.028) and 6 months (−0.633 vs −1.614; P = 0.018).
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Crater Lake, OR
With newer lipid emulsions, there is the potential to give more lipids and have less liver injury. A recent report by Diamond et al (JPEN J Parenter Enteral Nutr. 2016 Feb 2. pii: 014860711562692) provides some of the best data for the use of SMOFlipid in infants: Preventing the Progression of Intestinal Failure-Associated Liver Disease in Infants Using a Composite Lipid Emulsion: A Pilot Randomized Controlled Trial of SMOFlipid.
Here’s the abstract: and afterwards some slides from a recent lecture that I gave regarding parenteral nutrition associated liver disease (and intestinal failure associated liver disease):
To examine whether SMOFlipid prevents progression of intestinal failure-associated liver disease (IFALD) in parenteral nutrition (PN)-dependent infants with early IFALD (conjugated bilirubin 17-50 µmol/L, 1-3 mg/dL).
Pilot multicenter blinded randomized controlled trial comparing SMOFlipid with Intralipid. Patients received the trial lipid for up to 12 weeks, unless they achieved full enteral tolerance sooner. The primary clinical outcome was the serum conjugated bilirubin.
Twenty-four infants (mean age, 6 weeks) participated in the trial (13 Intralipid and 11 SMOFlipid). At the time of trial enrollment, patients in both groups were receiving 90% of their calories by PN. Mean duration on trial was 8 weeks and did not differ according to treatment (P = .99). At trial conclusion, patients who received SMOFlipid had a lower conjugated bilirubin than those who received Intralipid (mean difference, -59 µmol/L; P = .03). Patients receiving SMOFlipid were also more likely to have a decrease in serum conjugated bilirubin to 0 µmol/L than those in the Intralipid group over the entire observation period (hazard ratio, 10.6; 95%; P = .03). The time to achievement of full enteral tolerance did not differ statistically (hazard ratio, 1.3; P = .59) between the groups. There was no significant difference in safety outcomes between the groups.
Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.
Here are a few more slides from my recent lecture on PNALD/IFALD:
The above slide was borrowed from a talk by Dr. Conrad Cole on short bowel syndrome (available online via the Pediatric Nutritionist blog).
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A recent review (WS Lee, RJ Sokol. J Pediatr 2015; 167: 519-26) provides a good explanation of the role of various intralipids and intestinal microbial dysbiosis in the setting of intestinal failure-associated lipid disease (IFALD).
The review discusses criteria for IFALD (e.g. conjugated bilirubin ≥2 mg/dL & parenteral nutrition ≥14 days), the epidemiology, and the pathogenesis. Potential risk factors and level of evidence for these risk factors is noted in Table 1.
Table 2 describes the evidence supporting suggested strategies for the prevention of IFALD. The effectiveness and recommendation levels for these strategies are generally very low and weak based on reviews by ASPEN and the American Pediatric Surgical Association. Among the strategies, reduction of lipid emulsion to ≤ 1 g/kg/day has some of the strongest support in this table but is still regarded as level III evidence and described as “probably effective.” Other strategies reviewed included ethanol locks, multidisciplinary team management, use of ursodeoxycholic acid/bile acid supplementation, cycling of parenteral nutrition, use of prokinetics, removal of manganese and copper from parenteral nutrition, and antibiotic use to prevent bacterial overgrowth.
With regard to alternative intravenous lipids (eg. fish oil, or SMOF mixture):
- “Although a properly powered randomized controlled trial has not been conducted, current evidence suggests that the use of FO-ILE [fish oil -intravenous lipid emulsion] is effective in reversing the established cholestasis associated with IFALD, but there is insufficient evidence for a preventative effect in neonates.”
- “Most studies have been retrospective, used a historical comparison group, used different doses of lipid, and were conducted in patients with quite advanced IFALD.”
- Use of FO-ILE improves biochemical parameters, but has not been shown to “improve other important long-term clinical outcomes, such as severity of hepatic fibrosis.”
- In addition, reduced ILE and FO-ILE may result in other sequelae such as cognitive developmental delay. “Recently, lower brain weight and alterations of brain PUFA content were demonstrated in newborn piglets receiving total PN with reduced dose SO-ILE or FO-ILE compared with normal dose SO-ILE.”
My take: This review underscores how little is known about the approaches often recommended for management of IFALD.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. 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.
A recent publication in JPGN indicates that resuming low dose soy-based parenteral lipid can be effective in patients (n=7) whose cholestasis had resolved on a fish oil-based parenteral lipid. It does not resolve the larger question of whether fish oil-based parenteral lipids are truly more effective than soy-based parenteral lipids (see previous blog links below).
Here’s the abstract:
Objectives: Intestinal failure associated liver disease (IFALD) contributes to significant morbidity in pediatric intestinal failure (IF) patients. However, the use of parenteral nutrition (PN) with a fish oil-based IV emulsion (FO) has been associated with biochemical reversal of cholestasis and improved outcomes. Unfortunately, FO increases the complexity of care: as it can only be administered under FDA compassionate use protocols requiring special monitoring, is not available as a 3-in-1 solution and is more expensive than comparable soy-based lipid formulation (SO). Due to these pragmatic constraints a series of patient families were switched to low-dose (1 g/kg/day) SO following biochemical resolution of cholestasis. This study examines if reversal of cholestasis and somatic growth are maintained following this transition.
Methods: Chart review of all children with IFALD who switched from FO to SO following resolution of cholestasis. Variables are presented as medians (interquartile ranges). Comparisons performed using Wilcoxon signed-rank test.
Results: 7 patients aged 25.9 (16.2,43.2) months were transitioned to SO following reversal of cholestasis using FO. At a median follow up 13.9 (4.3,50.1) months there were no significant differences between pre- and post-transition serum alanine and aspartate aminotransferases, direct bilirubin, and weight-for-age z-scores. Due to recurrence of cholestasis, one patient was restarted on FO after four months on SO.
Conclusions: Biochemical reversal of IFALD and growth were preserved after transition from FO to SO in 6/7 (86%) patients. Given the challenges associated with the use of FO, SO may be a viable alternative in select home PN patients.
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Many have advocated for the use of parenteral fish oil lipids like Omegaven which are rich in omega-3 polyunsaturated fatty acids (O3FAs), though the data in support of them are limited (New lipid emulsions — lacking data to support usage …).
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.
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A quick glance at a recent study (JPGN 2014; 58: 438-42) suggests a favorable outlook for patients with ultra-short bowel syndrome (U-SBS). U-SBS has been defined as having a residual small bowel length <10 cm distal to the ligament of Treitz. A more cynical definition by a colleague years ago was that U-SBS was when patients can fart and burp at the same time.
Looking at the details: This study enrolled 11 patients into a prospective Italian database since 2000 and examined their outcomes. Inclusion criteria included U-SBS diagnosed in the neonatal period (<28 days) and necessitating home parenteral nutrition at discharge.
The demographics note that these patients were bigger at birth and less premature than typical series of patients with SBS:
- Only one of the patients had necrotizing enterocolitis as the sole underlying disease and six patients had volvulus.
- All but two had ≥50% of their colons, with five having their entire colon.
- All but one of these patients had gestational age ≥32 weeks and only two patients had documented birth weight less than 2300 gm.
The authors note that these patients currently receive SMOFlipid as outpatients and Omegaven as inpatients. All patients receive some enteral feedings. Loperamide is used selectively.
- Inpatient hospital care ranged from 23 to 104 days/year, but had improved during the last year of followup.
- With >5 years of followup, 2 of the 11 patients had died. One of these patients had severe intestinal failure associated liver disease (IFALD) despite use of Omegaven.
- One patient underwent isolated intestinal transplantation.
- No children in this series underwent a bowel-lengthening…”given the shortness of the residual small bowel, the gain of length after any procedure will not significantly improve absorption.”
Given their results, the authors note that despite recommendations for early referral for intestinal transplantation in patients with U-SBS, this may not result in a survival benefit. They note a study by Pironi et al (Gut 2011; 60: 17-25) that showed that among 80 intestinal transplant candidates, 5-year survival was greater in those who were not transplanted.
Bottomline: This small cohort shows that certain populations of U-SBS may do well clinically for a long time with medical management. Caution should be used in extrapolating these results to SBS patients with different demographics.