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Cholestasis
Neonatal Cholestasis
Neonatal cholestasis is defined biochemically as prolonged elevation of the serum levels of conjugated bilirubin beyond the first 14 days of life. Jaundice that appears after 2 wk of age, continues to progress, or does not resolve by this age should be evaluated and a conjugated bilirubin level determined.
Cholestasis in a newborn can be caused by infectious, genetic, metabolic, or undefined abnormalities giving rise to mechanical obstruction of bile flow or to functional impairment of hepatic excretory function and bile secretion (see Table 383.1 ). Mechanical lesions include stricture or obstruction of the common bile duct; biliary atresia is the prototypic obstructive abnormality. Functional impairment of bile secretion can result from congenital defects or damage to liver cells or to the biliary secretory apparatus.
Neonatal cholestasis can be divided into extrahepatic and intrahepatic disease ( Fig. 383.1 ). The clinical features of any form of cholestasis are similar. In an affected neonate, the diagnosis of certain entities, such as galactosemia, cystic fibrosis, sepsis, or hypothyroidism, is relatively simple and a part of most neonatal screening programs. In most cases, the cause of cholestasis is more obscure. Differentiation among biliary atresia and idiopathic neonatal hepatitis is particularly difficult.
Mechanisms
Metabolic liver disease caused by inborn errors of bile acid synthesis or transport is associated with accumulation of atypical toxic bile acids and failure to produce normal choleretic and trophic bile acids. The clinical and histologic manifestations are nonspecific and are similar to those noted in other forms of neonatal hepatobiliary injury. Autoimmune mechanisms may also be responsible for some of the enigmatic forms of neonatal liver injury.
Some of the histologic manifestations of hepatic injury in early life are not seen in older patients. Giant cell transformation of hepatocytes occurs commonly in infants with cholestasis and can occur in any form of neonatal liver injury. It is more common and more severe in intrahepatic forms of cholestasis. The clinical and histologic findings of patients with neonatal hepatitis and those with biliary atresia are somewhat similar, but there are distinguishing features. The basic process common to both is an undefined initiating insult causing inflammation of the liver cells or of the cells within the biliary tract. If the bile duct epithelium is the predominant site of disease, cholangitis can result and lead to progressive sclerosis and narrowing of the biliary tree, the ultimate state being complete obliteration (biliary atresia) . Injury to liver cells can present the clinical and histologic picture of “neonatal hepatitis.” This concept does not account for the precise mechanism, but it offers an explanation for well-documented cases of unexpected postnatal evolution of the disease processes; infants initially considered to have neonatal hepatitis, with a patent biliary system shown on cholangiography, can later manifest biliary atresia.
Functional abnormalities in the generation of bile flow can also cause neonatal cholestasis. Bile flow is directly dependent on effective hepatic bile acid excretion by the hepatocytes. During the phase of relatively inefficient bile acid transport and metabolism by the liver cell in early life, minor degrees of hepatic injury can further decrease bile flow and lead to production of atypical and potentially toxic bile acids. Selective impairment of a single step in the series of events involved in hepatic excretion produces the full expression of a cholestatic syndrome. Specific defects in bile acid synthesis are found in infants with various forms of intrahepatic cholestasis ( Table 383.1 ). Severe forms of familial cholestasis are associated with neonatal hemochromatosis, an alloimmune-mediated gestational (maternal antibodies against fetal hepatocytes) disease responsive to maternal intravenous immunoglobulin. Sepsis is known to cause cholestasis, presumably mediated by an endotoxin produced by Escherichia coli.
Table 383.1
Proposed Subtypes of Intrahepatic Cholestasis
From Balistreri WF, Bezerra JA, Jansen P, et al: Intrahepatic cholestasis: summary of an American Association for the study of liver diseases single-topic conference, Hepatology 42(1):222–235, 2005.
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Note: FIC1 deficiency, BSEP deficiency, and some of the disorders of bile acid biosynthesis are characterized clinically by low levels of serum GGT despite the presence of cholestasis. In all other disorders listed, the serum GGT level is elevated.
ADPLD, autosomal dominant polycystic liver disease (cysts in liver only); ARPKD, autosomal recessive polycystic kidney disease (cysts in liver and kidney); BAAT, bile acid transporter; BRIC, benign recurrent intrahepatic cholestasis; BSEP, bile salt export pump in; GGT, γ-glutamyl transpeptidase; PFIC, progressive familial intrahepatic cholestasis.
Evaluation
Identification of cholestasis warrants a prompt effort to accurately diagnose the cause ( Table 383.2 ). Although cholestasis in the neonate may be the initial manifestation of numerous and potentially serious disorders, the clinical manifestations are usually similar and provide few clues about the etiology. Affected infants have icterus, dark urine, light or acholic stools, and hepatomegaly, all resulting from decreased bile flow as a result of either hepatocyte injury or bile duct obstruction. Hepatic synthetic dysfunction can lead to hypoprothrombinemia and bleeding. Administration of vitamin K should be included in the initial treatment of cholestatic infants to prevent hemorrhage (intracranial).
Table 383.2
Value of Specific Tests in the Evaluation of Patients With Suspected Neonatal Cholestasis
| TEST | RATIONALE |
|---|---|
| Serum bilirubin fractionation (i.e., assessment of the serum level of conjugated bilirubin) | Indicates cholestasis |
| Assessment of stool color (does the baby have pigmented or acholic stools?) | Indicates bile flow into intestine |
| Urine and serum bile acid measurement | Confirms cholestasis; low level indicates inborn error of bile acid biosynthesis |
| Hepatic synthetic function (albumin, coagulation profile) | Indicates severity of hepatic dysfunction |
| α 1 -Antitrypsin phenotype | Suggests (or excludes) protease inhibitor ZZ phenotype |
| Thyroxine and thyroid-stimulating hormone | Suggests (or excludes) endocrinopathy |
| Lysosomal acid lipase enzyme activity | Suggests (or excludes) lysosomal acid lipase deficiency |
| Sweat chloride and mutation analysis | Suggests (or excludes) cystic fibrosis |
| Urine and serum amino acids and urine reducing substances | Suggests (or excludes) metabolic liver disease |
| Ultrasonography | Suggests (or excludes) choledochal cyst; might detect the triangular cord sign, suggesting biliary atresia |
| Liver biopsy | Distinguishes biliary atresia; suggests alternative diagnosis |
In contrast to unconjugated hyperbilirubinemia, which can be physiologic, cholestasis (conjugated bilirubin elevation of any degree) in the neonate is always pathologic and prompt differentiation of the cause is imperative. The top priority is to recognize conditions that cause cholestasis and for which specific therapy is available to prevent further damage and avoid long-term complications such as sepsis, an endocrinopathy (hypothyroidism, panhypopituitarism), nutritional hepatotoxicity caused by a specific metabolic illness (galactosemia), or other metabolic diseases (tyrosinemia).
Another potential treatable metabolic disease, lysosomal acid lipase deficiency (LAL-D), is a rare autosomal recessive lysosomal storage disease which results in a mutation in the lysosomal acid lipase (LIPA) gene. The mutation creates a decline in the LAL activity, resulting in accumulation of cholesteryl esters and, to a lesser degree, triglycerides in multiple organs, including the liver, spleen, adrenal glands, lymph nodes, intestinal mucosa, vascular endothelium, and skeletal muscle. Clinically, the disease can present in 2 major phenotypes: infantile-onset Wolman disease (WD) and later-onset cholesterol ester storage disease (CESD). LAL-D usually presents in infants with an acute-severe course progressing to liver failure. Sebelipase Alfa (recombinant human LAL enzyme) is approved for the treatment of patients with LAL-D.
Hepatobiliary disease can be the initial manifestation of homozygous α 1 -antitrypsin deficiency or of cystic fibrosis. Neonatal liver disease can also be associated with congenital syphilis and specific viral infections, notably echovirus and herpes viruses including cytomegalovirus. These account for a small percentage of cases of neonatal hepatitis syndrome. The hepatitis viruses (A, B, C) rarely cause neonatal cholestasis.
Mitochondrial disorders may present with acute neonatal hepatic failure, or cholestasis; prominent among these disorders are respiratory chain defects and mitochondrial DNA depletion syndromes ( Table 383.3 ).
Table 383.3
Phenotypic Classification of Primary Mitochondrial Hepatopathies
From Lee WS, Sokol RJ: Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes, J Pediatr 163[4]:942–948, 2013, Table 1, p. 943.
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NN, Navajo neurohepatopathy; OXPHOS, oxidative phosphorylation; RC, respiratory chain.
The final and critical step in evaluating neonates with cholestasis is to differentiate extrahepatic biliary atresia from neonatal hepatitis.
Intrahepatic Cholestasis
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