Genetic Testing For Pediatric Liver Diseases And Hepatobiliary Health – Praveen Kumar Conjeevaram Selvakumar, MD, Vera Hupertz, MD, Naveen Mittal, MD, Kris V. Kowdley, MD, and Naim Alkhouri, MD
Due to recent medical advances, more patients with childhood-onset liver disease who receive pediatric liver transplants are surviving to adulthood, creating a different challenge for adult-based primary care providers. Adolescents with pediatric liver disease are a unique group of patients with different strategies for evaluation and monitoring, treatment, complications, and comorbidities. This creates a critical need for a formal transition model and multidisciplinary team integration for the successful transition of these patients to adult care.
Genetic Testing For Pediatric Liver Diseases And Hepatobiliary Health
Thanks to advances in medical science and our understanding of inherited and acquired liver disease, more children with acquired or congenital liver disease are surviving into adulthood than 2 decades ago. Improvements in immunosuppression and surgery have improved the chances of liver transplant recipients reaching adulthood, with a 15-20 year survival rate of 75%.
Liver Function Tests (lfts): B Quick
The causes of cholestasis in children are different from adults (Figure 1). Cholestasis in children is caused by genetic defects that affect the synthesis, processing or secretion of bile, or by blockage of the bile ducts, a good example is biliary atresia.
Cholestasis in children can be caused by blockage of the bile ducts, such as biliary atresia (above), or defects in the production and elimination of bile acids and other bile materials (below).
With the increasing number of adult patients with childhood-onset liver disease, internists and hepatologists must be aware of these liver diseases and develop expertise in managing this group of patients. In addition, young people with childhood-onset chronic liver disease present different challenges such as pregnancy, medical compliance, and psychological changes throughout life.
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These patients need a “transition of care” rather than a “transfer of care.” Transition of care is a multifaceted process that considers a patient’s medical, educational, and psychological needs before handing them over to geriatric care physicians, whereas transfer of care is a process of administrative change for geriatric care without prior expertise. of care for the elderly. patients.
In this article, we discuss the most common types of childhood cholestatic disease and their impact and management in adulthood (Table 1). Other common or rare cholestatic diseases are beyond the scope of this article.
Biliary atresia is a progressive inflammatory fibrosclerosing cholangiopathy of unknown cause. Its prevalence varies by geographic region, ranging from 1 in 6,000 to 1 in 19,000, with the highest prevalence in Taiwan.
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Biliary atresia usually manifests in the first few weeks of life, with progressive cholestasis leading to failure to thrive and fat-soluble vitamin deficiency. About 20% of patients have congenital splenic, gastrointestinal, genitourinary, cardiac, and venous malformations.
The first-line treatment for biliary atresia is the establishment of bile flow by the Kasai procedure (hepatic portoenterostomy), where the jejunal organ is sutured to the liver in Roux-en-Y. The results of the Kasai procedure depend on the time of the operation, so timely diagnosis of biliary atresia is very important. When the Kasai procedure is performed within 60 days after birth, bile flow is achieved in up to 70% of patients; but if done after 90 days, bile flow is less than 25%.
The long-term outcome of biliary atresia in patients with congenital liver disease has been reported in several studies.
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743 patients with biliary atresia underwent the Kasai procedure at a median age of 60 days. Survival rates were 57.1% at 2 years, 37.9% at 5 years, 32.4% at 10 years, and 28.5% at 15 years. other subjects,
The 20-year transplant-free survival rate ranged from 23% to 46%. Therefore, at least one third of children with biliary atresia live to adulthood with their own liver.
Although the Kasai procedure improves bile flow, even after a successful Kasai procedure, up to 70% of patients develop complications of biliary atresia such as progressive fibrosis, cirrhosis, portal hypertension, cholangitis, and liver cancer.
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Portal hypertension with evidence of splenomegaly, thrombocytopenia, or ascites occurs in two-thirds of long-term survivors of congenital biliary and hepatic atresia and in 30% of variceal hemorrhage.
Therefore, patients with biliary atresia and signs of portal hypertension should undergo annual upper endoscopy for varicose veins. Management of variceal bleeding in these patients includes the use of octreotides, antibiotics, variceal closure, and sclerotherapy; Primary prevention can be achieved using beta blockers and endoscopic variceal ligation.
Cholangitis is common, occurring in 40% to 60% of patients with biliary atresia after the Kasai procedure, and approximately one quarter of these patients have multiple episodes.
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Patients with cholangitis should be adequately treated with oral or intravenous antibiotics depending on the severity of the presentation. The role of antibiotic prophylaxis remains unclear.
Pulmonary complications such as hepatopulmonary disease and portopulmonary hypertension can also occur in patients with biliary atresia who have a congenital liver. It is important for doctors to be aware of these problems and examine them, for example, echocardiography of excited salt for hepatopulmonary disease and echocardiography for portopulmonary hypertension. Timely observation is very important because the results of liver transplantation depend on the severity at the time of transplantation in these conditions, especially in portopulmonary hypertension.
There are no well-defined guidelines for the screening of adolescents with biliary atresia. Many centers recommend starting immediately after the Kasai procedure with abdominal ultrasound and alpha-fetoprotein measurement every 6 months or annually because hepatocellular carcinoma has been reported in children under 2 years of age.
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Transplantation. Adult hepatologists are faced with the difficult task of deciding when to transplant, balancing the long-term complications of biliary atresia with the risk of long-term immunosuppression after transplantation. In addition, young people with these disorders may have preserved synthetic function, resulting in low Model of End-Stage Liver Disease (MELD) scores, which can complicate the transplant listing process.
Extrahepatic manifestations include deformity of the butterfly vertebrae, facial dysmorphism (for example, low and turned down eyes characterized by a “triangle” of the fascia), posterior embryo-toxon (congenital eye defect characterized by opaque rim around the eye). cornea), peripheral pulmonary stenosis, renal insufficiency and vascular malformation.
Liver manifestations vary from asymptomatic laboratory abnormalities to progressive cholestasis beginning with untreated childhood pruritus, xanthoma, failure to thrive, and end-stage liver disease requiring liver transplantation in 15–20% of patients.
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Transplantation. Interestingly, the liver disease phenotype is already established in childhood, with little or no development in adulthood. Most children with mild liver disease resolve on their own, while those with severe cholestasis may develop progressive liver disease or cirrhosis requiring a liver transplant in childhood. Only a small proportion of children with mild cholestasis develop end-stage liver disease in late childhood or early adulthood.
Therefore, liver transplantation for liver disease secondary to essential cholestasis almost always occurs in childhood, usually between the ages of 1 and 4 years.
In a retrospective study comparing post-transplant outcomes in children with Alagille disease and biliary atresia, 1-year patient survival was better in children with Alagille disease, although Alagille was probably slightly inferior in children with atresia. of bile due to extrahepatic disease. syndrome and especially the use of immunosuppression for those with kidney disease.
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Similarly, 1- and 5-year patient survival outcomes with liver transplantation in adults with Alagille disease were also better compared to those who received liver transplantation for Alagille disease in childhood or biliary atresia in adults.
In the absence of cirrhosis, hepatocellular carcinoma has developed in these patients, which makes it almost impossible to implement predictive and monitoring strategies for them. Annual ultrasound examination and alpha-fetoprotein test can be used in patients with Alagille syndrome. However, due to the paucity of data, it will be difficult to determine which patients should undergo this test and when to start.
Heart disease. A cardiac phenotype is also often identified in childhood, with the pulmonary arteries most commonly involved.
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Conversely, kidney and other vascular problems can manifest themselves in adults. Renal manifestations vary and include structural abnormalities such as hyperechoic kidneys or renal tumors that may occur in childhood and some complications such as hypertension and renal artery stenosis that may occur in adults.
Neurological accidents such as stroke and intracranial hemorrhage can occur at any age, causing morbidity and mortality.
Therefore, some experts recommend magnetic resonance angiography every 5 years and before any major intervention to prevent these serious problems.
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Pregnancy. Successful pregnancies were recorded. Existing heart and liver disease can make pregnancy difficult, depending on the severity of the disease. Because it is an autosomal dominant inheritance pattern, the risk of the disease in newborns is 50%, so genetic counseling should be considered before pregnancy.
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive conditions associated with impaired bile formation leading to cholestatic liver disease in infants and young children. Three types have been described based on genetic changes in the hepatobiliary transport system:
PFIC 1 and 2 have low gamma-glutamyl transferase (GGT) cholestasis, while PFIC 3 presents with high GGT cholestasis.
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PFIC 1 and PFIC 2 usually cause cholestasis in infants, but PFIC 3 can cause cholestasis in late infancy, childhood, and even adulthood.
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