Hepatotoxicity in the treatment of acute lymphoblastic leukaemia

Serial liver function tests and percutaneous liver biopsies were performed on 21 children receiving treatment for acute lymphoblastic leukaemia (ALL). The patients received continuing chemotherapy either with daily 6-mercaptopurine and weekly methotrexate or with five-day pulses of these drugs every three weeks. Liver function tests were transiently abnormal in the majority of children, but the abnormalities bore no relationship to the histology of the liver biopsy. Mild inflammatory and fatty changes were commonly seen, and early portal fibrosis was found in three out of 16 patients biopsied at between 108–130 weeks on treatment. There was no correlation between treatment regime and results of biopsy. Three patients showed possible progression of abnormalities on repeat biopsy. The risk of development of portal fibrosis appears low after 2–3 years of continuing chemotherapy, but examination of liver histology may be indicated if more prolonged therapy is contemplated.     

Pretreatment liver biopsy in 20 children with histiocytosis X: a clinicopathologic correlation

Liver biopsies were done on 20 patients with histiocytosis X (HX) as part of pretreatment evaluation prior to entry on two Childrens Cancer Study Group protocols. Seventeen patients had hepatomegaly, and seven had one or more abnormal laboratory parameters using Lahey's criteria for liver dysfunction. Nineteen of 20 specimens showed various abnormalities of the portal triads. A single biopsy revealed normal liver. Among the changes were triaditis, bile duct proliferation, variable fibrosis with histiocytic infiltrates, and cirrhosis. One patient had typical granulomas of HX within the liver parenchyma in addition to portal triaditis. Patients with larger livers and dysfunction tended to show more marked histologic abnormalities in the portal triads. However, correlations among liver size, function, and pathology showed considerable overlap. Early death among these patients was more likely to be associated with progressive HX in other sites and/or infection. Death from cirrhosis and liver failure per se occurred in one patient 4 years after initial biopsy, but five other children had evidence of cirrhosis on biopsy or at autopsy. The majority of patients with triaditis initially did not have clinical evidence of progressive liver disease although four expired with other manifestations of HX or infection. Conversely, patients showing fibrohistiocytic changes or cirrhosis initially were likely to have continuing or progressive liver disease. Although the liver histology was not diagnostic of HX, the types of portal changes usually predicted the subsequent course of liver disease.     

Portal and Sinusoidal Fibrosis are Common on Liver Biopsy After Fontan Surgery

Hepatic fibrosis is an important complication after Fontan surgery in patients with single-ventricle congenital heart disease. Few reports of hepatic histology in these patients exist, and sinusoidal fibrosis has been described. We aimed to characterize fibrosis at liver biopsy procedure in patients with previous Fontan surgery and to identify patient variables associated with the degree of fibrosis. All patients who had previous Fontan surgery and who subsequently underwent liver biopsy at our institution between January 1990 and July 2010 were identified. For each biopsy specimen, portal and sinusoidal fibrosis were graded and medical records reviewed. Biopsy specimens from 13 patients were examined; the median time from Fontan surgery to liver biopsy procedure was 16.9 years (range 6.9–25). At the most recent biopsy procedure, 12 patients (92 %) had evidence of portal fibrosis, including 1 patient with portal-based cirrhosis. Thirteen patients (100 %) had at least some degree of sinusoidal fibrosis, including 1 patient with centrilobular-based cirrhosis. Lower platelet count was associated with greater degree of portal fibrosis by ordinal regression (odds ratio 0.84, P = 0.04), and patients with no or mild portal fibrosis had significantly higher platelet counts compared with those with moderate or severe portal disease (278 ± 78 K vs. 160 ± 46 K, P = 0.005). Four patients underwent serial biopsy procedures; portal fibrosis was progressed in 3 patients, and sinusoidal fibrosis was progressed in 3 patients. After Fontan surgery, portal and sinusoidal fibrosis are common at liver biopsy and can progress over time. Lower platelet count may represent a marker of portal-based disease in these patients.     

Liver histology after current intensified therapy for childhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are the main findings

BACKGROUND: During modern intensified therapy for childhood acute lymphoblastic leukemia (ALL) serum liver enzymes reach fairly high levels. Since no recent data on liver histopathology after therapy are available, we conducted a study of the subject. PROCEDURE: Liver biopsy specimens were evaluated and serum liver function tests and lipid profiles measured from 27 consecutive children, aged 3.5-17.6 years, treated according to the regimens for standard (SR) and intermediate risk (IR) ALL. RESULTS: None of the patients had entirely normal liver histology. Fatty infiltration was detected in 25 out of 27 (93%) and siderosis in 19 out of 27 patients (70%). Fourteen (52%) had both. Three (11%) also had mild portal and/or periportal fibrosis in addition to fatty change and siderosis. Fatty change was mainly microvesicular. Siderosis was in most cases grade II/IV to III/IV (in 16/19 or 84%). No hepatitis or cirrhosis was found. Serum total and LDL-cholesterol levels were higher in the patients with fibrosis than in the patients with fatty change (P = 0.036, P = 0.042) or with siderosis +/- fatty change (P = 0.036, P = 0.042). In serial ALT measurements a value of 300 U/L or more was oftener reached in the fibrosis than in the fatty change or siderosis groups (in 33 vs. in 12 or in 4% of the measurements, respectively, P = 0.014, in Kruskall-Wallis test). CONCLUSIONS: Microvesicular fatty change and siderosis are the main liver findings after current therapy for childhood ALL. Fibrosis occurs rarely. High values in serial serum ALT measurements repeatedly or a disturbed serum lipid profile may facilitate decisions about the need for a liver biopsy.     

Liver disease does not affect lipolysis as measured with the 13C-mixed triacylglycerol breath test in children with cystic fibrosis

BACKGROUND: Liver disease associated with cystic fibrosis may not only limit the solubilisation and absorption of the products of fat digestion, but also may depress the activity of pancreatic lipase. The purpose of this study was to measure the effect of liver disease on triacylglycerol lipolysis using the 13C-mixed triacylglycerol breath test. METHODS: Forty children with cystic fibrosis took 13C-mixed triacylglycerol with a standard breakfast and the child's normal pancreatic enzyme replacement therapy. Breath samples were collected before and every 30 minutes after ingestion for 6 hours. The cumulative percentage dose of 13C recovered at 6 hours was calculated from sequential measurements of 13C enrichment of breath CO2, measured by isotope ratio mass spectrometry. Liver abnormalities and portal hypertension were defined by ultrasound scan and clinical examination. RESULTS: Twenty-four children had liver abnormalities, including 5 with portal hypertension. No difference was found between cumulative percentage dose of 13C recovered at 6 hours in 16 children with no liver abnormality (mean, 21.4%+/-11.1%), 19 children with liver abnormalities (22.2%+/-10.0%) and 5 children with portal hypertension (20.9%+/-7.1%). CONCLUSION: Intestinal lipolysis is not reduced in cystic fibrosis liver disease when measured using the 13C mixed triacylglycerol breath test. These findings affirm the test's use as an indirect measure of fat digestion that is not affected by inadequate intraluminal bile salts or liver disease.     

Neonatal cholestasis as the presenting feature in cystic fibrosis

Between 1960 and 1994 cystic fibrosis was found in nine out of 1474 infants investigated for neonatal cholestasis. Four had delay in passing meconium. In all patients cholestatic jaundice was present during the first 48 hours and in three patients cholestasis was complete, mimicking biliary atresia. Serum cholesterol concentrations were normal in all but two children. Sweat chloride was repeatedly above 95 mmol/l in all instances. Three children had another condition enhancing the risk of cholestasis (alpha1-antitrypsin deficiency, hypopituitarism, perinatal asphyxia, and total parenteral nutrition). Liver histology displayed portal fibrosis and inflammation with bile duct proliferation; mucous plugs in bile ducts were observed in only one patient. Only one child died from cirrhosis. These results indicate that cystic fibrosis is not a major cause of neonatal cholestasis. However early signs of intestinal obstruction and low concentrations of serum cholesterol may indicate cystic fibrosis, regardless of liver histology. Neonatal cholestasis has no prognostic value concerning evolution to cirrhosis.     

Neonatal cholestasis as the presenting feature in cystic fibrosis.

Between 1960 and 1994 cystic fibrosis was found in nine out of 1474 infants investigated for neonatal cholestasis. Four had delay in passing meconium. In all patients cholestatic jaundice was present during the first 48 hours and in three patients cholestasis was complete, mimicking biliary atresia. Serum cholesterol concentrations were normal in all but two children. Sweat chloride was repeatedly above 95 mmol/l in all instances. Three children had another condition enhancing the risk of cholestasis (alpha1-antitrypsin deficiency, hypopituitarism, perinatal asphyxia, and total parenteral nutrition). Liver histology displayed portal fibrosis and inflammation with bile duct proliferation; mucous plugs in bile ducts were observed in only one patient. Only one child died from cirrhosis. These results indicate that cystic fibrosis is not a major cause of neonatal cholestasis. However early signs of intestinal obstruction and low concentrations of serum cholesterol may indicate cystic fibrosis, regardless of liver histology. Neonatal cholestasis has no prognostic value concerning evolution to cirrhosis.     

Hepatic toxicity of adjuvant chemotherapy for carcinoma of the breast

Four patients developed abnormal liver function tests and focal defects on liver scan while receiving cyclophosphamide, methotrexate and 5-fluorouracil as adjuvant chemotherapy following mastectomy for breast cancer. Liver biopsies showed severe focal inflammation. The biopsy findings and the subsequent clinical course of the patients strongly suggest that these abnormalities were due to hepatic toxicity of the chemotherapy and not metastic breast cancer. A review of serial liver function tests performed on 24 patients in that chemotherapy program revealed that four out of eight patients with elevated alkaline phosphatase prior to therapy developed early metastatic cancer. Elevated alkaline phosphatase occurring during chemotherapy on the other hand was quite common but more likely due to hepatic toxicity of the drugs. The development of abnormal liver function tests even in association with focal defects on liver scan is not sufficient to diagnose metastatic breast cancer in patients receiving adjuvant chemotherapy.     

Paediatric chronic liver diseases: how to investigate and follow up? Role of imaging in the diagnosis of fibrosis

Chronic liver diseases are rare in children, but encompass a wide spectrum of disorders that may all be complicated by liver fibrosis and therefore by portal hypertension. They may be classified according to the level of portal flow obstruction: prehepatic, intrahepatic or suprahepatic. Most of them, except presinusoidal diseases, may progress to cirrhosis that carries additional risks of impaired liver function and development of hepatocellular carcinoma. Imaging plays an important role in guiding the diagnosis and biopsy and for follow-up during treatment. US, with high-frequency transducers and Doppler, is the first modality of choice, directs the rest of the investigations and guides interventional radiology. MDCT has made great progress and has replaced angiography for diagnostic purposes. MRI is indicated for parenchyma and nodule characterization and for biliary tract evaluation. To avoid liver biopsy, several elasticity imaging techniques have been developed and have to be evaluated for accuracy and convenience in children. The role of each modality with main imaging findings is described in extrahepatic portal vein obstruction, hepatoportal sclerosis, congenital hepatic fibrosis, cirrhosis and Budd-Chiari syndrome.     

Congenital hepatic fibrosis in Saudi Arabia.

Congenital hepatic fibrosis (CHF) is a recognized cause of portal hypertension with oesophageal varices, gastro-intestinal haemorrhage and cholangitis in children without significant impairment of hepatic or renal function. This report describes the varied clinical presentation of CHF as seen at King Faisal Specialist Hospital and Research Centre (KFSH & RC) and emphasizes the clinical patterns that should enable a pediatrician to consider the diagnosis. Fourteen children with CHF were diagnosed between 1981 and 1988. The age at presentation ranged from 1.8-14 years (mean: 7.5 years); clinical manifestations at diagnosis were splenomegaly (12), hepatomegaly (11), failure to thrive (10), marked abdominal distention (4), and fever (4). Liver function tests were normal except for high alkaline phosphatase. Eight patients had polycystic kidneys confirmed on ultrasound examination. Upper gastro-intestinal endoscopy showed oesophageal varices of variable severity in all eight patients examined. Splenoportography revealed splenic vein occlusion in one patient. One patient died within days of admission with convulsions, coma, and aspiration pneumonia. One patient was lost to follow-up. The remaining 12 patients are all alive and receive regular follow-up. Two patients required splenorenal shunt. In view of the prevalence of consanguinity in Saudi Arabia, the diagnosis of CHF should be considered in children with hepatomegaly despite normal liver function tests, and particularly in those with renal abnormalities and/or evidence of portal hypertension.     

Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children and adolescents in the United States, and most probably also in the rest of the industrialized world.As the prevalence of NAFLD in childhood increases with the worldwide obesity epidemic, there is an urgent need for diagnostic standards that can be commonly used by pediatricians and hepatologists. To this end, we performed a PubMed search of the adult and pediatric literature on NAFLD diagnosis through May 2011 using Topics and/or relevant Authors as search words. According to the present literature, NAFLD is suspected based on the association of fatty liver combined with risk factors (mainly obesity), after the exclusion of other causes of liver disease. The reference but imperfect standard for confirming NAFLD is liver histology. The following surrogate markers are presently used to estimate degree of steatosis and liver fibrosis and risk of progression to end-stage liver disease: imaging by ultrasonography or magnetic resonance imaging, liver function tests, and serum markers of liver fibrosis.NAFLD should be suspected in all of the overweight or obese children and adolescents older than 3 years with increased waist circumference especially if there is a NAFLD history in relatives. The typical presentation, however, is in children ages 10 years and older. The first diagnostic step in these children should be abdominal ultrasound and liver function tests, followed by exclusion of other liver diseases. Overweight/obese children with normal ultrasonographic imaging and normal liver function tests should still be monitored due to the poor sensitivity of these tests at a single assessment.Indications for liver biopsy include the following: to rule out other treatable diseases, in cases of clinically suspected advanced liver disease, before pharmacological/surgical treatment, and as part of a structured intervention protocol or clinical research trial.     

Primary sclerosing cholangitis in children

Primary sclerosing cholangitis (PSC) in eight children, five males and three females between the ages of 4 and 13 years, presented with minimal clinical symptoms and few signs of liver disease. Diagnosis was made by a highly characteristic histology in all and additional endoscopic retrograde cholangiography (ERC) in four patients. Six children suffered from concomitant inflammatory bowel disease (IBD). Laboratory abnormalities consisted of mild elevation of transaminases and alkaline phosphatase, with marked elevation of immunoglobulin G in seven and detection of anti-nuclear antibodies in four of the eight children. In all cases, needle liver biopsy specimens revealed portal tracts considerably expanded by edema and chronic inflammation diagnostic of nonsuppurative cholangitis and nonsuppurative fibrosing pericholangitis. ERC showed decreased arborization in the whole biliary tree. In two patients, changes were confined to the intrahepatic portion of the biliary tract. No specific drug therapy was given to our patients. Those with concomitant IBD were treated with salazosulfapyridine (SASP). The clinical course has been mild in all patients up to now. It is concluded that PSC may be much more frequent in childhood than was considered before, especially in children with IBD.     

Endoscopic sclerotherapy for varices in children

Thirty-one children with variceal bleeding due to portal hypertension (extrahepatic obstruction 19, non-cirrhotic portal fibrosis five, and cirrhosis of liver seven patients) were treated with endoscopic sclerotherapy with absolute alcohol. Acute variceal bleeding was successfully controlled in 10 patients by emergency sclerotherapy. A 3 weekly schedule of sclerotherapy could achieve obliteration of varices in all the patients. The mean (+/- SD) number of sclerotherapy courses and the time required for variceal eradication was 4.5 +/- 1.7 and 14.4 +/- 3.9 weeks, respectively. During a mean follow-up of 23.3 +/- 11.4 months, variceal recurrence was seen in three (9.7%) patients, two with cirrhosis and one with noncirrhotic portal fibrosis. Recurrence was not seen in any patient with extrahepatic obstruction. Five (16.1%) patients had a rebleed that could be controlled with emergency sclerotherapy. Esophageal stricture developed in four (12.9%) patients and could be dilated easily in all of them. The other complications of sclerotherapy included retrosternal pain, dysphagia, and fever; these were mild and short lasting. Survival in patients with extrahepatic obstruction and noncirrhotic portal fibrosis was 100%. The only death was in a cirrhotic, who died due to terminal hepatic failure. In conclusion, endoscopic sclerotherapy can be recommended as a safe and effective treatment in children for the control of acute variceal bleeding and for variceal obliteration.     

Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis.

To evaluate the adverse effects associated with long-term methotrexate (MTX) therapy in children with juvenile rheumatoid arthritis, we conducted a retrospective review of 62 patients with polyarticular juvenile rheumatoid arthritis, treated from 84 to 296 weeks with MTX weekly. Pulmonary function testing was performed before MTX therapy on 46 patients older than 6 years of age; 26 patients had serial pulmonary function testing, and no abnormalities were detected. In all 62 patients, liver function (alanine aminotransferase and aspartate aminotransferase activity) was monitored every 3 months. Transient liver function abnormalities developed in nine patients during treatment. Twelve patients underwent percutaneous liver biopsies after receiving 815 to 2980 mg of MTX; none had fibrosis or cirrhosis. Macrocytic anemia developed in one child receiving simultaneous long-term trimethoprim-sulfamethoxazole therapy and resolved after the trimethoprim-sulfamethoxazole was discontinued. No stomatitis or rashes were observed. Six patients were able to discontinue MTX therapy when their disease remitted; 56 continue MTX therapy. No child permanently discontinued MTX therapy because of an adverse effect. These data suggest that MTX may be better tolerated in children with juvenile rheumatoid arthritis than in adults with rheumatoid arthritis.     

Hepatic steatosis: a frequent non-specific finding in HIV-infected children

Thirty HIV-infected children were cross-sectionally examined for morphologic hepatic abnormalities, using ultrasonography or histology. Abdominal ultrasonography was performed in 27 children. The liver structure was normal in four patients, one of whom had moderate symptoms of the HIV infection and three of them severe symptoms. Abnormal liver structure, compatible with hepatic steatosis, was found in 23 (85%) patients. Five of them were in an early stage of the HIV infection (category N or A), three patients were ranked in category B and 15 patients in category C. Histological examination of the liver was performed in 11 children and steatosis was documented in ten (91%). In seven (70%) of these ten children steatosis had been suspected by ultrasonography. In conclusion, steatosis is common in HIV-infected children. It is non-specific and has no impact on disease, diagnostic evaluation or management. Conclusion Ultrasonography is a sensitive, accurate, non-invasive screening tool. It is more reliable than liver function tests. Received: 28 January 1999 / Accepted: 16 June 1999     

An Observation from Liver Biopsies Two Decades Post-Fontan

This brief report describes an observation from liver biopsy results in nonfailing Fontan patients, currently in their second postoperative decade. In three patients, with either atriopulmonary or atrioventricular connections and functional left ventricles, we found no portal fibrosis. In contrast, we found portal fibrosis in three clinically similar, nonfailing Fontan patients with lateral tunnel connections and functional left ventricles. We recognize the results may be secondary to chance; nevertheless, we speculate about possible relevancy.     

Recurrent hemolytic-uremic syndrome. A report of two cases

Two boys suffering from the hemolytic-uremic syndrome (HUS) are presented. One of them developed four episodes of the disease beginning at infancy, the other one had at least two episodes which were associated with mild portal fibrosis of the liver. Between the attacks of the disease, the children were completely healthy, and no renal or hematological abnormalities were detected. Both patients are now physically and mentally well developed healthy young men. The relatioship between HUS and thrombotic thrombocytopenic purpura is briefly discussed.     

Retrospective review of cystic fibrosis presenting as infantile liver disease.

The mode of presentation, clinical course, and outcome of 12 infants with cystic fibrosis and liver disease referred over an 18 year period were investigated retrospectively. Median age at presentation was 6.5 weeks (range, 5-12). Two thirds were boys. Conjugated hyperbilirubinaemia was the presenting symptom in 11 patients, and hypoalbuminaemia in one. Jaundice was cleared over a median period of 7.36 months. Eight patients had bile duct proliferation on liver biopsy and one required cholangiography to exclude biliary atresia. Classic histological features of cystic fibrosis were only present in two children biopsied at 8 and 18 months. Three patients had meconium ileus, including one infant with concomitant alpha(1) antitrypsin deficiency, who required early liver transplantation. All other patients had no signs of significant chronic liver disease during a median follow up of 42 months (range, 10-205). Children with cystic fibrosis and infantile liver disease have a good short and medium term prognosis.     

Clinical utility of liver biopsy in children with acquired immunodeficiency syndrome

BACKGROUND: Little is known about hepatic histology in children with AIDS, although the liver is frequently involved in the course of HIV infection. The clinical utility of liver biopsy in these patients is not well-defined. We reviewed retrospectively the results of this procedure in a group of infected children better to delineate its indications. PATIENTS AND METHODS: Eighteen children with AIDS underwent liver biopsy in our institution. The indications were unexplained fever in eight children, six of whom had an elevated erythrocyte sedimentation rate and clinical suspicion of mycobacterial infection; jaundice in four; suspicion of drug toxicity (dideoxyinosine) in two; discussion of treatment for chronic hepatitis B in three; suspicion of cytomegalovirus infection in one who had also AIDS cholangiopathy. RESULTS: Of the six children thought to have mycobacterial infection, two had the disease on biopsy, both of whom had abnormal liver enzymes. The children with unexplained fever had nonspecific findings, except for one with lymphoid interstitial pneumonitis who had a dense lymphoid infiltrate. Of the four with jaundice two had extensive necrosis caused by adenovirus infection in one and suspected herpes simplex infection in the other. The other two with jaundice had unexplained findings, severe necrosis and fibrosis in one case and hemophagocytosis in the other one; both improved clinically. Both children with suspected dideoxyinosine hepatotoxicity had nonspecific findings. The three children with chronic hepatitis B had mild lesions that were not an indication for treatment. CONCLUSIONS: Liver biopsy appeared to be useful in two groups of selected children with AIDS: when there is strong clinical suspicion of mycobacterial infection; and when the child is jaundiced.     

Transient elastography for non‐invasive evaluation of post‐transplant liver graft fibrosis in children

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow‐up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non‐invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non‐invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100‐fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval ‐0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non‐invasive, reliable tool for the assessment of graft fibrosis in the follow‐up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.