Category Archives: Pediatric Gastroenterology Liver Disease

How to Identify Dubin-Johnson Syndrome

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Typically, most pediatric gastroenterologists want to remember that the gross appearance of the liver in patients with Dubin-Johnson is black as this is rumored to be a frequently asked question for board testing.  Practically, though other features are important to recognize since the color of the liver is not readily evident except during surgery.  As such, a recent retrospective study (T Togawa et al. J Pediatr 2018; 196: 161-7) describes 10 neonatal patients from Japan.

Key findings:

  • Only 3 of the 8 patients who underwent liver biopsy had a grossly black liver
  • All liver specimens showed no expression of multidrug resistance-associated protein 2 and increased expression of the bile salt export pump protein
  • Homozygous or compound heterozygous pathogenic variants of ABCC2/MRP2 (ATP-binding cassette subfamily C member 2/multidrug resistance-associated protein 2) were identified in all patients

The clinical course was similar in the patients:

  • Cholestasis self-limited/benign: “severe cholestasis developed in the neonatal period…reaching a maximum at 19 to 60 days. Cholestasis then decreased and disappeared at 2 to 9 months of age.”  Acholic stools were common during the cholestatic phase.
  • Serum AST and ALT remained consistently normal
  • There was no hepatosplenomegaly and no failure to thrive

My take: Dubin-Johnson syndrome is much easier to identify with the availability of genetic panels.

Related blog post: Dubin-Johnson Syndrome

 

Hereditary Fructose Intolerance

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A recent case series (Li H, A Diaz-Kuan, M Vos et al. Mol Genet Metab. 2018 Apr;123(4):428-432) highlights the importance of dietary history in infants with liver failure (abstract below).  Congratulations to my colleague Miriam Vos one of the coauthors.

Commentary on this publication from Emory News (from Kipp Ellsworth’s twitter feed):

Babies with inherited intolerance of fructose face a risk of acute liver failure if they are fed certain widely available formulas containing fructose, pediatricians and geneticists are warning. Baby formula manufacturers should remove fructose or sucrose, or explicitly label their products to allow parents to avoid those sweeteners if necessary, the doctors say.

In a recent paper in Molecular Genetics and Metabolism, Emory geneticists Hong Li, MD, PhD and Michael Gambello, MD, PhD together with Children’s Healthcare of Atlanta pediatric hepatologist Miriam Vos, MD and colleagues report four cases of hereditary fructose intolerance (HFI), all diagnosed in early infants. All had acute liver failure that resolved when the infants switched to formula without fructose.

HFI is estimated to occur in 1 out of 20,000 live births. It comes from mutations in the aldolase B gene, resulting in an inability to metabolize fructose. Early symptoms include nausea, vomiting, abdominal pain and failure of an infant to gain weight. If unrecognized, HFI can result in liver and kidney damage, seizures or death.

HFI-related problems do not appear if an infant is being breastfed exclusively. It is normally recognized when fructose-containing solid foods, such as fruit, are introduced into the diet several months after birth. However, some baby formulas – often soy-based – contain sweeteners such as high-fructose corn syrup or sucrose (table sugar), which is made of fructose and glucose linked together. Sometimes, the label only says “sugar” instead of sucrose…

Since HFI is a treatable disease, Li urges pediatricians to consider HFI as a potential diagnosis if there is a feeding problem, elevated transaminase enzymes or jaundice (a sign of liver damage) and the infant has been fed formula containing fructose or sucrose.

Some information about a young patient’s condition can be obtained from urine carbohydrate tests, but the only way to confirm HFI is by genetic sequencing.

Abstract:

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.

Related blog post: Changing Approach to Neonatal Acute Liver Failure

Chattahoochee River Near Island Ford

 

Lots of Allergy & Autoimmunity Issues Following Solid Organ Transplantation

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A recent retrospective cross-sectional cohort study (N Marcus et al. J Pediatr 2018; 196: 154-60, editorial page 10) identified 273 transplant recipients with a median followup of 3.6 years. This cohort included 111 liver transplant recipients, 103 heart transplant recipients, 52 kidney transplant recipients, and 7 multivisceral transplant recipients.

Key findings:

  • 92 (34%) developed allergy or autoimmunity after transplantation.
  • Allergic problems included eczema (n=44), food allergy (n=22), eosinophilic gastrointestinal disease (n=11), and asthma (n=28)
  • Autoimmunity problems developed in 6.6% (18) including autoimmune cytopenias (n=10). Two patients died due to autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis.
  • Allergic problems typically developed during the first year after transplantation and rarely after 5 years following transplantation.
  • ~20% required a change in immunosuppression
  • ~50% improved with time

In the editorial, the Dr. Helen Evans notes that the increasing reporting of atopic/allergic disorders could be due to recognition but could also be due, in part, to the widespread adoption of tacrolimus instead of cyclosporine for immunosuppression.

My take: Many have said that organ transplantation, which is life-saving, substitutes one problem for another.  This is an example of an additional burden, often related to immunosuppression, that patients and families have to manage afterwards.

Chattahoochee River, Island Ford

More on Time to Split (2018)

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As noted in a blog last year (More on its Past Time to Split), increased use of split livers can reduce liver transplantation waitlist mortality in children.  Further justification for this approach is evident from a new study (DB Mogul et al. J Pediatr 2018; 196: 148-53, editorial pg 12) indicated that outcomes following split liver organs are equivalent to whole organ liver organs.

The authors examined two time periods: 2002-2009 and 2010-2015 using the Scientific Registry of Transplant Recipients. n=5715

Key findings:

  • 1-year survival from split liver transplant (SLT) improved during the later period compared to the initial period: 95% versus 89%. n=1626 (28.5% of all transplants)
  • 1-year survival from living donor liver transplant (LDLT) improved during the later period compared to the initial period: 98% versus 93%. n=661 (11.6% of all transplants)
  • 1-year survival from whole liver transplant (WLT) was essentially unchanged during the later period compared to the initial period: 95% versus 94%. n=3428 (60% of all transplants)

These data show that survival after transplant is no longer worsened by SLT and may be higher for LDLT than WLT.

The editorial by Dr. Bae Kim and Dr. Vakili note that there have been several proposals to encourage more use of SLTs.  One that was developed “would prioritize children <2 years old before local/regional adults except for those who were status 1 or who had a MELD score above 30.”  At this point, these efforts to favor SLT allocation have not been adopted by UNOS Board of Directors.

My take (borrowed from editorial): “The question should no longer be ‘To split or not to split?’ but rather ‘Why should we let children die when we can now split livers safely?'”

Related blog posts:

Chattahoochee River

 

 

Are Long-Term Liver Transplant Survivors Destined to Have Low Bone Density? (No)

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Briefly noted: A recent study (L Ee et al. JPGN 2018; 66: 797-801) provides some good news for children who have had liver transplantation (LTx).

Among 42 patients (64% with biliary atresia) who had undergone LTx at a median age of 2.2 years and were long-term survivors (median time since LTx 10.1 yrs), mean bone mineral density (BMD) were normal.  Lumbar BMD z-score -0.15 and total body BMD -0.76.  Pathologic fractures were noted in 2 patients; these occurred within 18 months of transplantation.

My take: this study indicates that over time, most patients are not likely to have very low bone density.

Liver Shorts May 2018

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VL NG et al. J Pediatr 2018; 196: 139-47. This study with 148 children examined the neurodevelopmental outomes of young children with biliary atresia (ChiLDRen Study). Key finding: Children with their native livers were at increased risk for neurodevelopmental delays at 12 and 24 months.  This risk was more than 4-fold increased among those with unsuccessful Kasai procedure.

Related blog posts:

WS Lee et al. J Pediatr 2018; 196: 14-20. Updated review on hepatopulmonary synddrome (HPS) and portopulmonary hypertension (POPH).  Figure 1 graphically shows the difference in pathophysiology.  HPS hallmark is intrapulmonary vascular dilatation.  POPH is characterized by progressive remodeling of the wall (thickening & vasoconstriction) of small pulmonary arteries.

Related blog posts:

JA Woo Baidal et al. Hepatology; 2018; 67: 1339-47. This prospective cohort study with 528 children showed that increased Vitamin E intake in early childhood, based on validated food questionnaires, correlated with lower ALT values in mid-childhood.  Children with higher intakes “had lower odds of elevated mid-childhood ALT” (adjusted odds ratio of 0.62) when comparing quartiles 2-4 to the lowest quartile.  The authors note that Vitamin E is present in foods that are more often consumed in “healthful diets, such as wheat germ, almonds, spinach, and broccoli, as well as cooking oils.”

J Pfeiffenberger et al. Hepatology 2018; 67: 1261-69. The retrospective multicenter study with 282 pregnancies in 136 women with Wilson’s disease (WD), showed good outcomes. Aggravation of neurologic symptoms was rare (1%) (though tended to persist), liver test abnormalities (6%) resolved in all cases after delivery. Birth defect rate of 3% and spontaneous abortion rate of 26%; rthough, patients receiving treatment with zinc and D-penicillamine had lower spontaneous abortion rates, (10% and 17%, respectively) than those without treatment.  Chelation therapy resulted in no increase in the rate of birth defects compared to the general population.

Related blog posts:

F Bril et al. Clin Gastroenterol Hepatol 2018; 16: 558-66. This prospective study of adults with biopsy-proven NASH (52 with diabetes and 49 with prediabetes) found that pioglitazone treatment was associated with a reduction in the primary outcome, NAFLD activity score by 2 or more points, in 48% of those with type 2 diabetes and 46% of those with prediabetes. And, with a resolution of NASH in 44% and 26% respectively.

 

Big Creek Greenway near McFarland

When Should a Spleen Guard Be Recommended?

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A survey (O Waisbourd-Zinman, et al. JPGN 2018; 66: 447-49) of 44 pediatric hepatologists (with 935 years of clinical practice) examined the issue of splenic rupture and spleen guards.  ~90% of those surveyed reported following at least 30 patients with portal hypertension and splenomegaly.

  • In total, the hepatologists could recall 13 cases of splenic rupture among patients with portal hypertension/splenomegaly due to cirrhosis –almost all of these occurred after a fall or in a motor vehicle accident.  Only one of these falls happened during a sports-related event (soccer).
  • 11 cases were serious. 9 of these cases resulted in shock with subsequent splenectomy, embolization, and/or death. Death reported in 2 cases.
  • In this survey,  61% of hepatologists recommended “absolute restriction from activity with high risk of blunt abdominal trauma;” whereas 23% indicated that activities with risk of blunt trauma were acceptable if wearing a spleen guard.
  • To prevent splenic rupture in patients with portal hypertension/splenomegaly, among the participating hepatologists, the majority identified the following ‘high risk’ sports: football (95%), hockey (82%), and wrestling (66%).  A smaller percentage advocated a spleen guard for skiing (42%), soccer (41%), basketball (30%) and other sports.

While I did not participate in this survey, the one patient with chronic liver disease that I followed who had a splenic rupture had fallen down a flight of steps; fortunately, he recovered with supportive care.

My take: This survey shows that there is wide variability in the use of spleen guards.  In almost all cases of splenic rupture, this was precipitated by severe trauma.  Though, patients with portal hypertension may avoid high contact sports and thus the risks are for these sports is unclear.

Related blog post:

Foggy Morning in Sandy Springs

Wilson’s Disease –Pediatric Guideline

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P Socha et al. JPGN 2018; 334-4. This ESPGHAN position paper makes recommendations for Wilson’s disease. This is a helpful paper, though the AASLD Wilson’s guideline is more comprehensive. A couple of pointers from the JPGN publication:

  • The authors recommend molecular testing if available and using liver copper measurement “if molecular testing is inconclusive”
  • Screen siblings of any new patients
  • Urinary copper excretion in the 200-500 mcg per 24 hours is consistent with adequacy of treatment
  • With treatment, liver function tests improve over 2-6 months. “If increased transaminases remain or relapse despite treatment, poor compliance should be suspected.”

Related blog posts:

 

January 2018 -Sunrise in Sandy Springs

TPN Prior to Liver Transplantation for Biliary Atresia

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Briefly noted:

D Wendel et al. JPGN 2018; 66: 212-7.  This single center retrospective review examined patients who received home TPN prior to liver transplantation.   These 18 patients, which represented 41% of their entire transplant cohort of 44 between 2010-2015, all had biliary atresia. Key findings:

  • Malnutrition improved or resolved in all but one patient
  • 8 catheter-related infections were noted (3.8/1000 catheter days)
  • There were no deaths in patients receiving TPN

My take: While there is an increased burden of care with TPN, improved nutrition may improve long-term outcomes.

Related blog posts:

Amber Cove, Dominican Republic

 

 

Double-Blind Randomized SMOFLipid Study

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A recent double-blind randomized study (A Repa et al. J Pediatr 2018; 194: 87-93) compared a mixed lipid emulsion (SMOFlipid) to a soybean-oil lipid in 223 extremely low birth weight infants. Median time on parenteral nutrition was ~23 days.

Key findings:

  • The primary outcome of parenteral nutrition associated cholestasis (PNAC) was NOT significantly different in the two groups: 10.1% for SMOF and 15.9% for control group (P=.20).
  • No other outcome measures were affected, including ROP, BPD and growth.

The authors note that even the control group had less cholestasis than previous cohorts and indicated that the use of probiotics and possibly more aggressive enteral feeds were at work.

My take (borrowed in part from authors): These results “cannot be generalized to infants with substantially longer time on PN.” However, this study shows that SMOFlipid alone will not prevent cholestasis, which is well-known to be multifactorial.

Sandy Springs