Alpha-1 antitrypsin (AAT) deficiency is an autosomal recessive genetic disease that can lead to a number of different medical conditions. Chronic liver disease, cirrhosis, and hepatocellular carcinoma may result from the accompanying accumulation of a variant of AAT protein in liver cells. Among babies with AAT deficiency who come to medical attention, neonatal cholestasis is one of its most common presentations. Sometimes called neonatal cholestatic hepatitis or neonatal hepatitis syndrome, neonatal cholestasis typically resolves on its own, but its highly variable progression can, in rare cases, lead to severe complications, such as cirrhosis, portal hypertension, and liver failure. On the other hand, even some infants with AAT deficiency who don’t exhibit neonatal cholestasis can develop liver failure later in childhood.1
According to one of the world’s leading authorities on neonatal cholestasis, Jeffrey Teckman, MD, a pediatric gastroenterologist and a professor in the Department of Biochemistry and Molecular Biology at the Saint Louis University School of Medicine, a typical presentation could look like this: “A baby would come in with prolonged jaundice, longer than you would expect from physiologic jaundice. The baby’s still yellow when it’s 2 weeks old. And the pediatrician or the primary care doctor does blood tests and finds out that it’s not physiologic jaundice. It’s actually cholestatic jaundice. Something’s wrong with the liver.”
“There are 200 different conditions that can cause that clinical picture, but, of those 200, AAT deficiency is, in fact, one of the most common,” Dr. Teckman notes. “And so, if a newborn is diagnosed with neonatal cholestasis, a test for AAT deficiency should be the very next test.” Liver disease can also be detected, he adds, via hepatosplenomegaly that’s discovered during a routine physical examination, or through the use of liver function tests.
Not an easy thing to predict
In order to better define the natural history and clinical variability of cholestatic liver diseases, including AAT deficiency, the Childhood Liver Disease Research Network (ChiLDReN) conducted the Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC) at 17 pediatric centers in the U.S. and Canada.2 LOGIC was a prospective study of children and young adults with AAT deficiency that evaluated potential predictors of portal hypertension, liver transplantation, and death. From 2007 through 2017, the study enrolled participants starting at birth to age 25 years who had AAT deficiency and evidence of liver disease. The primary outcomes were “the onset of either definite, or possible, clinically evident portal hypertension and liver transplantation or death.”2
LOGIC enrolled 350 participants, of whom 60% were male, with a median baseline age of 4.2 years (interquartile range 7.9 years, range 0.1 to 24.9 years), who were followed up for a median of 2.5 years (range 0 to 9.7 years). At study entry, 72 participants (21%) had definite/possible clinically evident portal hypertension. Of the rest, 18 developed definite/possible portal hypertension during follow-up, for an incidence rate of 2.1 per 100 person-years. Thirty-two participants had a liver transplant or died during 1077 person-years of follow-up, for an annual incidence rate of 3.0 transplants per 100 person-years. One death resulted from definite/possible portal hypertension and another occurred after transplant. Of the 30 participants who had a liver transplant, 29 had definite/possible portal hypertension at study entry, and all of them developed portal hypertension before transplant.
No statistically significant difference was found for either definite/possible portal hypertension-free survival or liver transplant-free survival based on the presence of neonatal cholestasis. The incidence of both portal hypertension and liver transplantation or death increased slowly over time. The probability of developing definite/possible portal hypertension for all participants at 2 years was 5% (95% confidence interval [CI] 2% to 9%), and the 2-year probability of liver transplant or death was 8% (95% CI 5% to 11%).
Some 28% of participants with a history of neonatal cholestasis had definite/possible portal hypertension during the study, compared with 21% without a history of neonatal cholestasis (P=.16); the hazard ratio in those with neonatal cholestasis compared with those without was 3.70 (95% CI 1.06 to 12.87; P=.04). Twelve percent of patients with a history of neonatal cholestasis underwent a transplant or died during follow-up, compared with 7% without a history of neonatal cholestasis; the hazard ratio for liver transplantation or death for those with neonatal cholestasis versus those without was 1.93 (95% CI 0.89 to 4.17; P=.09).
Patients with AAT should be followed closely
This study looked carefully at the natural history of infants and children with AAT deficiency and liver disease, with a focus on portal hypertension, which is the most common severe liver disease outcome seen in this population. Although prior studies from other countries suggested that most infants with AAT deficiency who present with neonatal cholestasis get better on their own, and that only a minority of them develop portal hypertension, this hadn’t yet been studied in North America. It was also unknown whether infants or children who came to medical attention but did not have neonatal cholestasis were still at risk for portal hypertension.
Regarding the latter subgroup, Dr. Teckman, the lead author of the LOGIC study, says, “It was widely thought that they were probably not at very great risk for portal hypertension, but our study showed the opposite: There is significant risk of portal hypertension in children, even if they don’t have neonatal cholestasis. So, while neonatal cholestasis is common, it doesn’t necessarily mean you’re going to get portal hypertension, and the absence of neonatal cholestasis doesn’t mean you’re not going to get portal hypertension.”
Therefore, Dr. Teckman urges all clinicians to follow infants with AAT deficiency closely and consistently. This suggestion is especially important, he says, because despite the lack of a cure for AAT deficiency, “we do have many effective treatments for liver problems, and we’re able to mitigate the damage of complications that occur.”
- 1. Patel D, McAllister SL, Teckman JH. Alpha-1 antitrypsin deficiency liver disease. Transl Gastroenterol Hepatol. 2021;6:23. doi:10.21037/tgh.2020.02.23.
- 2. Teckman J, Rosenthal P, Hawthorne K, et al. Longitudinal outcomes in young patients with alpha-1-antitrypsin deficiency with native liver reveal that neonatal cholestasis is a poor predictor of future portal hypertension. J Pediatr. 2020;227:81-86.e4. doi:10.1016/j.jpeds.2020.07.031.