Viral hepatitis in children: what do we know in 2021?

Viruses are a common cause of hepatitis in children. Hepatitis A and E cause acute infections while Hepatitis B, C and D can lead to chronic infection with increased morbidity and mortality due to chronic liver disease and hepatocellular carcinoma in later life. Acute infections may be fulminant causing acute liver failure necessitating a liver transplant. Our understanding of these viruses continues to evolve, and this review aims to summarize the current strategies in diagnosis, prevention and use of anti-viral drugs to treat these infections.     

Liver transplantation in a case of hypoproteinemia and coagulopathy

A female infant with hypoproteinemia and coagulopathy associated with hypertyrosinemia was successfully treated with living-related liver transplantation (LRLT). On the 12th day of life plasma amino acid analysis revealed a marked elevation of tyrosine, so the patient was fed on a low-tyrosine and low-phenylalanine diet. However, hepatosplenomegaly. hypotonia, alopecia, eczema and psychomotor delay did not improve and recurrent episodes of disseminated intravascular coagulation (DIC) caused her condition to deteriorate. Liver biopsy on the 230th day revealed marked fatty change accompanied by mild to moderate cholestasis. Therefore. LRLT from her father was performed on the 286th day resulting in improvement of all the aforementioned signs and symptoms. Despite a thorough examination, no diagnosis of a known disorder could be established. However, her elder brother had also been born with severe hypoproteinemia and coagulopathy, and died of DIC on the second day of life. Thus, the disorder is designated as a new entity, namely ‘congenital hypoproteinemia and coagulopathy associated with hypertyrosinemia’.     

Lectin-reactive alpha-fetoprotein in tyrosinaemia type I

Despite the introduction of NTBC into the treatment of tyrosinaemia type I (TT1) and a considerable improvement in the outcome of these patients, the principal risk of developing hepatocellular carcinoma (HCC) in this metabolic disorder remains mainly in those children with late introduction of NBTC after the second year of life. Serial total alpha-Fetoprotein (AFP) levels are used to evaluate the individual risk to develop malignant changes. A failure of AFP to decrease on adaequate treatment or a secondary increase after a period of falling levels have been an indication for liver transplantation. Lectin-reactive alpha-Fetoprotein is a recently described marker to distinguish hepatocellular carcinoma from benign liver disease in adult cirrhotic patients. AIMS: To investigate if the analysis for Lectin-reactive alpha-Fetoprotein would lead to earlier detection of HCC compared to a judgement based on the evolution of standard total AFP alone. PATIENTS: We report the analysis of 12 patients with TTI and histologically proven HCC. There of 5 were diagnosed under one year of age, but NTBC treatment was started between 2 years 3 month and 7 years of age except in one case in which NTBC was introduced when the diagnosis of TTI was made. The remainder of the patients cover up to the age of 15 years. All patients had been treated with NTBC. METHODS: Lectin containing agarose gel for AFP electrophoresis leads to AFP separation according to different affinities of the varying carbohydrate chains of AFP to lectins. RESULTS: AFP subfractions could be identified in all 12 patients. In 6 patients the L3-AFP rose before the total AFP. In 3 patients the rise in L3-AFP was consistent with the rise of the total AFP and in 3 patients the L3-AFP was raised after the total AFP or did not increase at all. DISCUSSION: We were able to identify 6 out of 12 patients who had an early increase of L3-AFP before they developed a change in total AFP levels. The clinical significance of these early changes need to be determined. Lectin-affinity electrophoresis may have a potential role as an additional tool that may help to discriminate benign liver disease from HCC in TTI. CONCLUSIONS: We suggest the further evaluation of lectin-reactive AFP in TTI.     

Current status of liver tumors in children

Most tumors of the liver in children are malignant. Benign tumors occur most often in infants, are usually vascular, and seldom require surgery. Hepatoblastoma and hepatocellular carcinoma are the most common malignant tumors. Hepatoblastoma affects younger children and hepatocellular carcinoma affects older children and adolescents. Treatment consists of surgical resection before or after chemotherapy, and long-term survival is impossible without resection. Survival rate exceeds 80% in children with hepatoblastoma. Children with hepatocellular carcinoma and other more unusual malignant tumors do not do as well. Current treatment plans are described for both benign and malignant tumors of the liver.     

Cytoplasmic Inclusion Bodies and Minimal Hepatitis: Fibrinogen Storage without Hypofibrinogenemia

A 12-year-old Japanese boy had chronic elevation and fluctuation of serum transaminase levels since infancy, with no signs or symptoms of liver failure. Usual infections or metabolic disorders were eliminated from consideration. No coagulopathy or abnormality in plasma concentrations of clotting factors was found. Light microscopy of liver biopsy specimens obtained at ages 2, 5, and 7 years showed slight hepatocyte disarray and minimal mononuclear-leukocyte lobular inflammation, with eosinophilic inclusion bodies in the cytoplasm of hepatocytes throughout the lobule. These bodies stained with the periodic acid-Schiff (PAS) technique; the PAS-positive material was partly diastase digestible and on immunostaining marked for fibrinogen but not for α₁-antitrypsin. On transmission electron microscopy, the bodies were represented by finely granular material contained within membranes and were interpreted as tentatively endoplasmic reticulum. Fibrinogen storage may be manifest as minimal hepatitis without coagulopathy. Received August 12, 1999; accepted June 27, 2000.     

Managing acute liver failure

Acute liver failure in childhood is a rare but fatal disease with a mortality of 70% without transplantation. The aetiology depends on age. In neonates, sepsis or an inherited metabolic liver disease is most likely, whereas viral hepatitis or drug-induced liver failure, especially following paracetamol overdose, is common. The clinical presentation includes jaundice, coagulopathy and encephalopathy. Early diagnosis is essential in order to prevent complications such as cerebral oedema, gastrointestinal bleeding and renal failure. Poor prognostic features include a reduction in liver size, a rising bilirubin with fall in hepatic transaminases, and increasing coagulopathy. Early supportive management, particularly intravenous N-acetylcysteine, may be effective but, in most instances, liver transplantation will be the definitive treatment and thus early referral to a specialist unit for liver transplantation is mandatory.     

Acute renal failure in Reye's syndrome.

Three patients with initial clinical manifestations and biochemical findings suggestive of a diagnosis of Reye's syndrome had acute renal insufficiency develop and had evidence of consumptive coagulopathy, not generally considered features of the syndrome. As a group, they could not be distinguished, either on the basis of their clinical manifestations or liver pathologic findings, from the 17 patients with Reye's syndrome without renal failure seen in our institution during the same period of time. The use of osmotic diuretics in an effort to decrease cerebral edema may be life threatening in these patients with compromised renal function since hypervolemia, cardiac failure, and worsening of cerebral edema may occur.     

Hepatoblastoma in a child with progressive familial intrahepatic cholestasis

End-stage liver cirrhosis because of metabolic or infectious diseases predisposes to hepatic malignancies like hepatocellular carcinoma. We report the first case of hepatoblastoma incidentally detected in the explanted liver of a 2-yr-old child undergoing liver transplantation for cirrhosis because of progressive familial intrahepatic cholestasis (PFIC). The diagnosis was difficult to obtain. The hepatoblastoma was not seen on ultrasound examination of the cirrhotic liver. As we could confirm retrospectively, alpha fetoprotein (AFP) was found elevated prior to transplantation. Two years after successful transplantation, there are no signs of malignancy detectable by clinical and radiological methods. We conclude from this case that PFIC may induce hepatoblastoma and that children with liver cirrhosis should undergo routine screening of serum AFP concentration.     

Hemophagocytic Syndrome Presenting as Acute Hepatic Failure in Two Infants: Clinical Overlap with Neonatal Hemochromatosis

Two patients with hemophagocytic lymphohistiocytosis who presented with acute liver failure are reported. Both presented with fever, hepatosplenomegaly, markedly elevated liver function tests, abnormal coagulation profiles, and an increase in serum ferritin. Both infants were diagnosed with neonatal hemochromatosis based on a clinical picture of hepatic insufficiency with hyperferritinemia and were referred for liver transplantation. The first patient died of liver failure and septicemia before transplantation. Review of autopsy material revealed a hepatitis-like pattern and extensive infiltration of liver and other organs including bone marrow by histiocytes, some of which were hemophagocytic. The second patient underwent liver transplantation but died 44 days thereafter from progressive hemophagocytic lymphohistiocytosis. Examination of the resected liver demonstrated a hepatitis-like pattern, proliferation of histiocytes, and hemophagocytosis, and the bone marrow revealed hemophagocytic histiocytosis. Hemophagocytosis recurred in the allograft. Hepatic manifestations are common in hemophagocytic lymphohistiocytosis and overt hepatic failure may occur, but initial presentation as fulminant hepatic failure is not well recognized. Elevated serum ferritin can make the distinction from neonatal hemochromatosis and other forms of neonatal liver failure difficult. Hemophagocytic lymphohistiocytosis should be considered in the differential diagnosis of neonatal liver disease, especially when it is accompanied by cytopenias. Received May 5, 1998; accepted August 31, 1998.     

Neonatal hemochromatosis. A cause of liver failure in utero. Report of two cases and review of the literature

Neonatal hemochromatosis is a rare clinical pathologic entity, defined by severe neonatal liver failure of intrauterine onset associated with intra-and extra- hepatic siderosis that spares reticuloendothelial system. It is the most frequently recognized cause of liver failure in neonates. The cause is unknown but it may develop secondary to abnormal fetoplacental iron handling or perinatal liver disease or be familial or as a consequence of gestational alloimmune disease. It's a syndrome with a common feature rather than a single pathologic entity, with maternal transmission and a high recurrence in the sibship. Death from multisystem organ failure usually occurs in the first few days or weeks of life. We report two newborn with neonatal hemochromatosis. The first died for multiorgan failure, despite aggressive support. The second underwent to liver transplantation. Since 1993, an antioxidant-chelator cocktail has been used in addition to standard supportive care, but this remains controversial. By 2002, a preliminary report suggested that treatment with weekly intravenous immunoglobulin during the later half of pregnancy, for woman whose most recent gestation was affected with proven NH. The diagnosis is suspected in the presence of severely impaired hepatic synthetic function accompanied by high serum ferritin levels, but is confirmed only by demonstration of increased hepatic iron stores, and extra-hepatic siderosis shown by autopsy or in vivo, which can be achieved by biopsy of the minor salivary glands or magnetic resonance imaging. Neonatal hemochromatosis is the most common specific indication for liver transplantation in the first three months of life and appears to be the treatment of choice, and must as well be considered as soon as it becomes apparent that medical support, which should include chelation-antioxidant treatment, is ineffective, before irreversible neurological complications appear.     

Complications of hemorrhagic stroke in children

The complications of hemorrhagic stroke in children begin first with one's failure to establish the correct diagnosis or from the lack of knowledge of attendant phenomena and second, from those events which occur before, during or because of the treatment provided for specific lesions. The fundamental principles of history gathering, clinical evaluation and appropriate neuroimaging will direct safe, uncomplicated patient care. This paper will examine those complications which may arise during the treatment of pediatric aneurysm, arteriovenous malformation and venous angiomas, newborn intraventricular hemorrhage, and cerebral hemorrhage associated with either a preexistent coagulopathy or neoplasm.     

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and early-onset liver cirrhosis in two siblings

We present the clinical, pathological, biochemical, and molecular results on an infant girl with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and data on her deceased elder brother for whom this condition was retrospectively diagnosed. Clinical signs were liver enlargement and elevated liver enzymes, failure to thrive, and neurological disease (coma, seizures) triggered by an infectious stress. In the second child hepatic failure and status epilepticus developed during the onset of a rotavirus gastroenteritis. A barbituric coma was induced, but hypotonia and lack of eye pursuit persisted after suppression of antiepileptic drugs. She ultimately died of heart failure. Unlike previously reported cases, both of these patients had early-onset cirrhosis, and severe neurological disease was observed in the second child. Conclusion Liver cirrhosis and brain damage may be underestimated in cases of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and may occur early in life. Received: 1 November 1998 and in revised forms: 10 April 1999 and 10 September 1999 / Accepted: 1 October 1999     

Experience with NTBC therapy in hereditary tyrosinaemia type I: an alternative to liver transplantation

We present the clinical data of five infants with type I (hepato-renal) tyrosinaemia on NTBC therapy. All presented initially at the local hospital in the 1st year of life with progressive abdominal distension owing to hepato-splenomegaly and with radiological evidence of liver cirrhosis, except for one child who was diagnosed during screening because of an affected sibling. Age at commencement of NTBC therapy ranged from 6 to 30 months. All infants showed remarkable improvement within 2-6 months of starting NTBC treatment, except one who died 2 months after commencement of therapy from uncontrolled liver failure, severe coagulopathy and Streptococcus pneumoniae septicaemia. NTBC treatment along with a phenylalanine- and tyrosine-restricted diet has effectively reversed most clinical manifestations of this disease. To date, none of our patients has developed hepatic carcinoma and NTBC was well tolerated without side-effects. NTBC is costly but life-saving and is an obvious alternative to more hazardous liver transplantation.     

Liver transplantation in tyrosinaemia type 1: the dilemma of timing the operation

Four children with tyrosinaemia type 1 received liver transplants. The metabolic disorder was corrected and all four had normal liver function on an unrestricted diet. Two children, transplanted at age five and seven years, proved to have occult hepatocellular carcinoma and both subsequently developed pulmonary metastases. One child was well 32 months after removal of a single pulmonary metastasis but the other child died with multiple metastases. The two younger children, transplanted at age 19 and 21 months, were well 28 and 44 months after operation, one after a second liver transplant. Our experience confirms the high risk of hepatocellular carcinoma in this disease and the potential value of early liver transplantation.     

Indications and outcome of liver transplantation in tyrosinaemia type 1

A retrospective analysis was performed on 17 patients presenting with tyrosinaemia type 1 (TT1) between 1989-1997; 7 pre 1992 prior to the introduction of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) therapy and 10 post 1992. During this time, eight children (5 males) underwent orthotopic liver transplantation (OLT); six prior to the introduction of NTBC in 1992 and two on NTBC therapy. The primary indications for OLT pre-1992 were risk of hepatocellular carcinoma with evidence of hepatic dysplasia in all, associated with liver failure in two, and rise in !-fetoprotein (AFP) in four. Two of the ten treated with NTBC required OLT. The indications were non-response to NTBC in one child and development of hepatic dysplasia associated with poor quality of life in the second patient. Median age for OLT was 64 months (range 5-127 months) with a median weight of 24 kg (range 6-25 kg). The histology of hepatectomy specimens at transplantation showed: cirrhosis in 8, hepatic dysplasia in 6 and hepatocellular carcinoma in 1. Plasma tyrosine and AFP returned to normal in all cases. Urinary succinylacetone reduced but persisted in small amounts (median 7.7 7mol/mmol creatinine). Hypertrophic cardiomyopathy resolved in 3/3 patients. Hypoglycaemia, not responding to dietary therapy or NTBC treatment, resolved post-transplant in one patient. There were two deaths, one from primary non-function and one from chronic rejection. Late complications in survivors (n=6) include post-transplant lymphoproliferative disease of the iris in one child which resolved and renal dysfunction with a fall in glomerular filtration rate in three (50%). Median follow up post OLT is 6.7 years (range 1-7 years). Quality of life post-transplant in survivors is good with unrestricted diet in all. Conclusion Liver transplantation is an effective treatment for TT1 with good quality of life. The current indications of OLT in TT1 are non-response to NTBC, risk of malignancy and poor quality of life related to dietary restriction and frequency of blood sampling.     

Hepatocellular carcinoma in Alagille's syndrome: a family study

Alagille's syndrome is a common form of familial intrahepatic cholestasis. In addition to the hepatobiliary system, many other organ systems are affected. Most of the affected patients survive through adulthood. Hepatic involvement is the cause of death in about one-third of patients. Hepatocellular carcinoma complicating the course of this disease is very rare and has been reported previously in only three cases. We report a family in which three of four siblings with this syndrome developed hepatocellular carcinoma and died as a result of it. None of these children had a liver disease, other than Alagille's syndrome, that could account for the development of such a tumor. This experience suggests that Alagille's syndrome, or at least chronic cholestasis, may be a predisposing factor for the development of hepatocellular carcinoma. Annual determination of alpha-fetoprotein and abdominal computed tomography (CT) scan may detect the development of a hepatocellular carcinoma in such cases while they are still resectable.     

Inborn errors presenting with liver dysfunction

In neonates, inborn errors of metabolism can produce all the major signs of liver dysfunction – jaundice, coagulopathy, hepatomegaly, splenomegaly, ascites and encephalopathy. The significance of encephalopathy in the neonate is different from that in older patients; it is usually due to a specific abnormality such as hypoglycaemia rather than being a non-specific indicator of liver failure. Attention is focused on five neonatal presentations: unconjugated hyperbilirubinaemia, cholestatic jaundice with otherwise good liver function, severe liver dysfunction (jaundice, coagulopathy persisting after vitamin K, and ascites), hepatomegaly with hypotonia± cardiomyopathy; and hepatosplenomegaly. The metabolic disorders presenting in these ways are listed alongside specific clinical features that can aid differential diagnosis and tests that can be used to confirm or refute the diagnosis. Diagnosis is important because treatment can be dramatically effective, e.g. withdrawal of galactose in galactosaemia. Even when treatment is not effective it is often possible to offer prenatal diagnosis for future pregnancies.     

Liver disease in children with cystic fibrosis

Identification, evaluation and treatment of liver disease are increasingly important challenges in children with cystic fibrosis (CF). Liver disease usually presents at puberty and is receiving more attention with improved life expectancy. The abnormal CF transmembrane regulator protein in the apical surface of the biliary epithelium causes the disease. Hyperviscous bile accumulates in the biliary tree causing cholangiocyte and hepatocyte injury, stimulating focal fibrosis. Fibrosis is thought to lead on to cirrhosis over a period of years, a process which is usually asymptomatic. Steatosis and biliary tree anomalies including cholecystitis also occur. Clinical signs of liver disease appear late, by which time cirrhosis may be established. Early diagnosis would allow interventions to be evaluated but there is no gold standard for screening. Currently, regular clinical assessment, measurement of liver enzymes, ultrasound and liver biopsy are all used to evaluate liver disease in CF. Bile acid therapy reverses many markers of the disease but there is no good evidence that progression to cirrhosis can be prevented. A few children with cirrhosis decompensate (demonstrated by falling plasma albumin or coagulopathy) but they do well with liver transplantation. Children with portal hypertension as the sole manifestation of CF liver disease can be effectively managed with a programme of variceal obliteration or porto-systemic shunts.     

Recombinant factor VIIa improves coagulopathy caused by liver failure

OBJECTIVE: Coagulopathy is an important cause of morbidity and mortality in patients with liver failure. The benefit of traditional therapies to correct coagulation is often limited and short-lived. Our aim is to identify indications for rFVIIa use and the outcome of treatment in children with liver failure. METHODS: A retrospective review from July 2000 to December 2001 was performed to identify consecutive patients with acute or chronic liver failure who received rFVIIa. Prothrombin times (PT) before and after therapy were compared by paired t test. RESULTS: Fifteen patients were treated with rFVIIa for coagulopathy caused by liver failure. All were receiving fresh frozen plasma (mean infusion rate, 39.7 mL/kg/day) when rFVIIa therapy was started. The mean PT before rFVIIa was 32.0 +/- 7.0 seconds. One hour after infusion, the PT normalized to 13.7 +/- 2.4 seconds (P < 0.0001) and remained significantly reduced at 6 hours (19.8 +/- 5.3 seconds; P < 0.0001). A sustained improvement was maintained during the subsequent 3 days. Five of seven patients with bleeding complications improved clinically after rFVIIa treatment. Two of the bleeding patients also benefited from improved fluid balance as fresh frozen plasma support was reduced. No thrombotic events were attributed to rFVIIa therapy. CONCLUSIONS: In patients with liver failure, rFVIIa therapy quickly normalizes the PT and maintains improved hemostasis, even when coagulopathy has been refractory to fresh frozen plasma. Therapy subjectively reduces clinical bleeding and can improve fluid balance, without complications.     

Screening newborns for galactosemia using total body galactose oxidation to CO2 in expired air

Classic galactosemia is caused by impaired galactose-1-phosphate uridyltransferase (GALT EC 2.7.712). If discovered and treated within the first days of life, the acute problems of hepatocellular damage, sepsis, and death are prevented. However, chronic problems such as ataxia, tremor, dyspraxic speech, and ovarian failure may occur. To determine whether screening newborns before discharge from the nursery for GALT deficiency is feasible and whether acute and chronic signs could be prevented by earlier intervention, we developed a simplified "breath test." We quantitated total body oxidation of C-D-galactose to CO2 in expired air by normal newborns between 2 h and 2 mo of age and compared their results to older children with GALT deficiency. We found no differences in total body galactose oxidation (TBGO) among normal newborns up to 48 h of age, but a 2-fold rise in TBGO developed during their first 2 wk of life. Older children with galactosemia had significantly less oxidative capacity than normal newborns. We conclude that newborn breath testing for total body galactose oxidation is feasible before discharge from nursery. It has potential utility for both preventing acute neonatal toxicity and determining the mechanisms producing long-term complications such as ovarian failure, dyspraxia, ataxia, and tremors.