The first lecture by Dr. Melissa Gilbert was an excellent overview of the genetics of Alagille Syndrome.
JAG1 mutations account for ~95% of Alagille syndrome mutations and NOTCH2 about 3%
Many mutations identified are due to missense mutations which are often variants of unknown clinical significance (VOUS). In these patients, to determine if it is pathogenic, one has to correlate the clinical picture along with specific amino acid change, location of variant, and frequency of variant in normal population. Dr. Gilbert noted that among the ~97% of cases with genetic abnormalities, about 80% have recognized pathogenic mutations and about 17% have VOUS.
There is variability of severity of Alagille syndrome in the same family, likely related to genetic modifiers
When using genetic panel, if panel uses only single nucleotide variants, this will miss the deletion/duplication variants which account for ~10% of cases
The second lecture by Binita Kamath was a terrific review and compared the differences between Alagille Syndrome with JAG1 mutations and NOTCH2; the latter are much less likely to have cardiac abnormalities and butterfly vertebrae. The liver phenotype/survival is similar.
Outcomes of Alagille syndrome by 25 years of age including frequent bone fractures and development of portal hypertension.
Severe liver disease is common. 75% in a multi-center cohort (CHILDREN) required liver transplantation by age 18 years and 10% died; in contrast, a large GALA cohort of 911 children, 41% survived with their native liver at 18 years.
After transplantation, renal sparing strategies are needed due to frequent renal insufficiency; patients with severe cardiac disease may not be candidates for liver transplantation.
There is work on an Alagille Syndrome growth curve.
Screening for brain vascular malformations/Moyamoya –Dr. Kamath tends to screen after age 8 years of age at baseline (when child does not need sedation for brain imaging) and then every 4-5 years. Also, an MRI/MRA is done prior to major surgery.
Hyperlipidemia in Alagille Syndrome is mainly due to lipoprotein X; this is not a risk factor for cardiac health.
The third (& also excellent) lecture by Saul Karpen (who disclosed his potential conflicts of interest) reviewed current treatments and emerging treatments.
The current medical therapies have not been carefully tested; rifampin for pruritus may relieve cholestasis in about 50% of patients.
IBAT inhibitors interrupt enterohepatic circulation. These agents improve pruritus and decrease serum bile acids.
Dr. Karpen reminded the audience to follow fat soluble vitamin levels and if treatment is needed, to provide Vitamin D formulations with TPGS.
After the start of immunosuppressive therapy, bilirubin, albumin, and INR normalized in 70%, 77%, and 69%, respectively, in a median of 2.6 months, 3 months, and 4 weeks, respectively, in patients with A-AIH and AS-AIH
Deterioration of liver function (bilirubin, INR) after 2 weeks of treatment should lead to rapid evaluation for LT and consideration of second-line medication.
The cumulative incidence of waitlist mortality was 5.2%. Median waitlist time was 83 days.
In multivariable analysis (n = 2253), increasing bilirubin level ( P < .001), portal vein thrombosis ( P = .03), and ventilator dependence ( P < .001) at listing were associated with a higher risk, whereas weight ≥10 kg at listing ( P = .009) was associated with a lower risk of waitlist mortality.
In this retrospective study with 31 children with Wilson’s disease (most of whom had had previous penicillamine), those who received more than 20 mg/kg/day of trientine therapy had increased adverse effects compared to those who received less than 20 mg/kg/day: 63% vs 7%; median followup was 60 months. In addition, there was not increased response to higher doses. The authors note that trientine had lower incidence of adverse effects compared to penicillamine and “appears to be the preferred” as a first-line treatment.
In this prospective cohort with 350 participants (all with either PiZZ (90%) or PiSZ (10%) and native livers), 278 (79%) entered the cohort (in 2007 or later) without portal hypertension and 18 developed portal hypertension during follow-up. Portal hypertension was defined by development of ascites, varices or combination of splenomegaly/thrombocytopenia. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. Median length of followup was 2.5 years. My take: While most children with Alpha-1-Antitrypsin Deficiency do well, monitoring is warranted as some will develop progressive liver disease (even in the absence of neonatal cholestasis).
In this phase 2 double-blind study with 78 patients with NASH, at week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%) (P=.002). Fibrosis improvement (1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). And, NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20)
This prospective study followed the natural history of NAFLD in children with timed liver biopsy reassessment in children (n=122) using the placebo arms of 2 large multicenter clinical trials; patients received standard of care lifestyle advice. The study population had a mean age of 13 years; 71% were Hispanic participants
At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH
Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH
Fibrosis improved in 34% of the children but worsened in 23%
Progression was more likely with increasing ALT, increasing GGT, type 2 diabetes/increasing HgbA1c
Overall, one-third had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.
The study conclusions are limited by selection bias, potential liver biopsy sampling errors, limited enrollment of non-Hispanic children, and relatively short duration of follow-up
~6% of children and 10% of adults develop severe liver complications of SCD
With sequestration, indications include pain with acute drop in hemoglobin (>2 g/dL)
Acute hepatic crisis is often signaled by elevated conjugated bilirubin
With severe liver disease/liver ischemia, authors advocated for exchange transfusion which “more efficiently decreases HbS percentage, faster restoring the blood flow than simple transfusion.” Consider after excluding biliary complication if INR is >1.4 with increased conjugated bilirubin (>3 mg/L). “Simple transfusion should be discussed in other cases.”
Cholangiopathy and autoimmune liver disease
Although autoimmune sclerosing cholangitis/autoimmune hepatitis are rare, it may account for 8% of children with SCD referred for hepatic dysfunction
Liver biopsy, needed for diagnosis, “is a dangerous procedure in SCD, which cannot be performed without at least a transfusion”
“Steroids can induce sickle crisis”
Look for ANA, SMA, LKM, and ANCA
“It is not usually a significant concern in children…In our patients, the median ferritin level was about 3000 ng/mL, and none had a severe overload on MRI”
Need to consider hepatitis B, hepatitis C, and hepatitis E in particular
Inquire about herbal medicines and recreative drugs
Results are often poor.
Problems include sickle cell crisis in the transplanted liver, and drug toxicity which can add to the neurological and renal morbidities of SCD
Stem cell transplantation
Consider for severe complications of SCD including hepatic complications
It is very difficult to try to understand potential toxic substances in our environments. Some of the reasons for this are that there are always numerous simultaneous exposures and harm from substances can accrue over long periods. Once a substance is identified, it can take a long time to develop convincing evidence and even longer time frames to try to enact policy changes.
Background/Methods: Per- and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. PFAS chemicals have a myriad industrial/household applications which include nonstick cookware and products that confer resistance to stains. According to the editorial (MC Cave, pg 1518-21), some refer to PFAS as “forever chemicals” due to their decades-long half-lives.
The study authors used data from 1105 mothers and their children (median age 8.2 years) from the European Human Early-Life Exposome cohort. Key findings:
High prenatal exposure to PFAS resulted in children who were at higher risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21–1.92)
PFAS exposure is associated with alterations in key amino acids and lipid pathways characterizing liver injury risk.
I have a deep admiration and fondness for Jorge. When I first did a gastroenterology rotation during my pediatric residency, he was the first person who handed me an endoscope and showed me how to handle it. During my training as a resident and as a fellow (1991-1997), I had the opportunity to get to know Jorge; for some of that time, he was completing his training as he started his GI fellowship in 1990.
I really enjoyed reading this introduction to learn a lot more about Jorge, because I don’t remember Jorge speaking about himself. Of course, he has been part of some very important advances in pediatric hepatology including the very useful MMP-7 assay, the ‘Jaundice chip’ and the START study.
The article delves into some personal attributes including the description of Jorge being ‘the Pele of pediatric hepatology’ (per Dr. Ronald Sokol). It also describes his family and some characteristics. “He has inspired us with his calm demeanor, decency, humor, positivity, and kindness.”
It is a personal thrill for me to read about one of my heroes in our field.
This retrospective study from Finland details the bone health of children with biliary atresia (BA). Key findings:
Out of 49 patients, 7 (14%) were diagnosed with rickets during infancy. Clearance of jaundice [odds ratio 0.055, 95% confidence interval [CI] 0.00266–0.393; P < 0.01] was a protective factor against rickets.
In DXA measurements, median lumbar spine aBMD anthropometrically adjusted z-scores were as follows:
in native liver survivors 0.8 (interquartile range [IQR] −1.9 to 1.4) at 5 and −0.3 (IQR −1.3 to 0.8) at 10 years
in liver transplanted patients 0.4 (IQR −0.2 to 1.1) at 5 and 0.6 (IQR −0.1 to 1.3) at 10 year.
Most BA patients have aBMD within normal range between 5 and 10 years of age irrespective of liver transplantation status.
My take: This study shows that early in life there is frequent bone impairment in children with BA. This generally improves in most children as cholestasis resolves (with or without liver transplantation).
Methods: A state-transition model of chronic HCV was developed to conduct a cost-effectiveness analysis comparing treatment at age 6 years vs delaying treatment until age 18 years
After 20 years, treating 10 000 children early would prevent 330 cases of cirrhosis, 18 cases of hepatocellular carcinoma, and 48 liver-related deaths
The incremental cost-effectiveness ratio of early treatment compared to delayed treatment was approximately $12 690/quality-adjusted life-years gained and considered cost-effective
My take (=conclusion from authors): Delaying treatment until age 18 years results in an increased lifetime risk of late-stage liver complications. Early treatment in children is cost effective. Our work supports clinical and health policies that broaden HCV treatment access to young children.
Related blog posts:
Hepatitis C in 2020: NASPGHAN Position Paper -includes the following: “We recommend treatment be considered and offered to all children with chronic HCV as early as 3 years of age with currently approved and anticipated DAA combination therapies”