Hepatic presentations of mitochondrial DNA depletion syndrome in children: A single tertiary liver centre experience.

Mitochondrial DNA depletion syndromes (MDDS) are a heterogeneous group and the hepato-cerebral phenotype is highly variable. A single centre retrospective study of all patients with MDDS presenting between January 2002 and September 2019. In total, 24 (13 male) children were identified: 7 POLG, 7 DGUOK, and 10 MPV17. Median age at presentation was 3 months (0.06-189). Sixteen had acute liver failure (ALF) and eight chronic cholestasis and/or raised transaminases. Four POLG patients developed liver injury after starting sodium valproate; Six DGUOK patients had neonatal ALF (median age 12 days), liver involvement developed at a median age of 2.5 and 11 months with MPV17 and POLG patients, respectively. Eighteen patients showed neurological involvement. Liver histology from 10 patients showed variable degrees of necrosis, steatosis, cholestasis, and fibrosis. Mitochondrial respiratory chain enzymology was abnormal in 5. Seventeen patients died at a median age of 8 months (range, 1-312) after a median time of 5.6 months from presentation: 5/7 POLG at 53 months, 7/7 DGUOK at 8 months and 5/10 MPV17 at 8 months. Three patients with MPV17 mutations received liver transplant (LT) at a median age of 24 months (range 5-132): all alive at 19, 18 and 3 years post-LT. Mutations in DGUOK and MPV17 genes are associated with a severe clinical phenotype characterised by early-onset/neonatal ALF or rapidly progressive cholestasis and death before 12 months of age. A subset of MPV17 patients was amenable to LT. Consideration for LT in infantile ALF remains difficult and rapid genetic testing is advised.

Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

Contrast enhanced ultrasound (CEUS) characterization of grey-scale sonographic indeterminate focal liver lesions in pediatric practice.

PURPOSE: To determine the usefulness of contrast-enhanced ultrasound (CEUS) in characterizing grey-scale sonographic indeterminate focal liver lesions (FLL) in pediatric practice. MATERIALS AND METHODS: Local Ethics Board approval waiver was attained. Consent for CEUS examinations was acquired from parents. Forty-four children referred for CEUS assessment of grey-scale sonographic indeterminate FLL over a 5-year period underwent standard multiphase CEUS performed by experienced operators. A phospholipid microbubble agent was used and low mechanical index ultrasound imaging techniques employed. Interpretation by consensus of the CEUS examination was compared to consensus interpretation of other imaging and to histology. Follow-up imaging was used to confirm stability of benign abnormalities. Any contrast reactions were recorded. RESULTS: The CEUS examination interpretation agreed with reference imaging in 29/34 (85.3 %) of cases. In discordant cases, reference imaging showed no abnormality (n = 5), with fatty change (n = 4) and regenerating nodules (n = 1) on CEUS and follow-up sonography. Where reference imaging was not performed (n = 10), histology (n = 7) or follow-up sonography (n = 3) confirmed the diagnosis. In one discordant case, all imaging modalities showed concordance identifying a malignant lesion; however histology demonstrated a benign hepatocellular adenoma. The specificity was 98.0 % (95 % CI; 86 - 100 %) and the negative predictive value was 100 %. No adverse effects to the contrast material were noted. CONCLUSION: These findings demonstrate the usefulness of CEUS in characterizing indeterminate grey-scale sonography FLL in pediatric patients with the potential to reduce exposure to ionizing radiation.

Germline APC mutations are not commonly seen in children with sporadic hepatoblastoma.

Hepatoblastoma is the most common primary liver tumor in childhood and occurs more commonly in families with familial adenomatous polyposis. Germline mutations of the gene responsible for familial adenomatous polyposis--adenomatous polyposis coli (APC)--are described in patients with hepatoblastoma even without a family history. We investigated children presenting with apparently sporadic hepatoblastoma between 1991 and 2004. Blood samples were available from 29 children (18 boys) whose conditions were diagnosed at a median age of 22 months (range 6-119 months). No germline APC mutations were found, which does not support the need for routine screening in sporadic hepatoblastoma in the absence of a suggestive family history of colorectal cancer or suspicion of familial adenomatous polyposis.

Response to varicella immunization in pediatric liver transplant recipients.

BACKGROUND: Individuals undergoing therapeutic immunosuppression are at risk of severe varicella-zoster virus (VZV) infection, particularly those without evidence of previous infection. METHODS: Eleven children, median age 10 months (range 5.5 months to 7 years and 9 months) received one dose of varicella vaccine (Varilrix, SmithKline Beecham plc, UK) before liver transplantation (median interval 95 days, range 40-289 days). The serological response to varicella vaccine was evaluated retrospectively and matched with the outcome and management of any subsequent exposures to VZV. RESULTS: Three children responded postimmunization, six children showed no response, and in two children the outcome was difficult to interpret having received blood products. Four children required varicella-zoster immunoglobulin prophylaxis posttransplantation, two of whom developed mild chickenpox. CONCLUSIONS: Only 3 of 11 children developed a clear antibody response to varicella vaccine. Administration of varicella vaccine did not affect the management of subsequent VZV exposures.

Role of HLA compatibility in pediatric liver transplantation.

BACKGROUND: The influence of HLA mismatching in liver transplantation remains controversial. To date, few studies have focused solely on the pediatric population, and none have investigated DR and DQ mismatches using molecular genotyping. We sought to investigate HLA-A, -B, -DR, and -DQ mismatches in a large series of primary pediatric liver transplant recipients. Living-related liver transplants were excluded. METHODS: A total of 138 consecutive first liver transplants performed between January 1991 and July 1996 were studied. Minimum follow-up was 1 year, and both patient and graft survival rates were assessed. The incidence of the most common complications was analyzed. HLA-A and -B phenotyping was performed by complement-dependent microcytotoxicity or polymerase chain reaction (PCR)-sequence-specific primer protocols in 133 of 138 patients. HLA-DR and -DQ genotyping was performed by standard PCR-sequence-specific oligonucleotide and/or PCR-sequence-specific primer protocols in 135 patients. RESULTS: Overall, there was no influence of HLA mismatching on either graft or patient survival rates. However, patients with two mismatches at the A locus showed a significantly lower incidence of acute rejection than those with one A mismatch (52% vs. 72%; P < 0.03) and patients with two B locus mismatches had a better graft survival rate at 5 years than those with one mismatch (76% vs. 62%), although this was of only borderline significance (P < 0.09). No differences were found in the severity of the episodes of rejection, incidence of chronic rejection, cytomegalovirus hepatitis, and other causes of graft loss. CONCLUSION: This study indicates that HLA-A, -B, -DR, and -DQ mismatches are not detrimental in primary pediatric liver transplantation.

Recurrence of Langerhans cell histiocytosis in the graft after pediatric liver transplantation.

Two girls were diagnosed with Langerhans cell histiocytosis (LCH) at the age of 16 and 7 months and developed end stage chronic liver disease related to LCH-induced sclerosing cholangitis at 28 and 8 months, respectively. They received liver transplants at 34 and 14 months of age. Five months post-orthotopic liver transplantation (OLT) one of the patients developed posttransplant lymphoproliferative disease, successfully treated with a combination of surgery and reduction of immunosuppression. Fourteen months post-OLT she developed diabetes insipidus, bilateral ear discharge, and new osteolytic lesions. After transplantation both girls had mild skin reactivations of LCH, requiring minimal steroid increments. At 60 and 5 months post-OLT intrahepatic LCH recurrence was diagnosed on the basis of abnormal biliary enzymes and presence of Langerhans cells in the grafts. Initial cholangiography in both patients was unremarkable. LCH activity was controlled by maintenance chemotherapy with vinblastine, etoposide, and prednisolone. Ten months after reappearance of LCH in the liver graft a follow-up cholangiography in one of the girls demonstrated a low grade cholangiopathy. Residual elevation of liver enzymes probably represents an ongoing pathogenic process.

Gender matching and outcome after pediatric liver transplantation.

BACKGROUND: Gender is not a selection criterion for orthotopic liver transplantation (OLT), and reports in adults have shown a less favorable outcome for male recipients of female organs; the only pediatric study did not support this finding. The aim of the present study was to assess the impact of donor and recipient gender on graft and patient survival rates after pediatric OLT. METHODS: We have reviewed retrospectively 137 children (male=63; median age: 3.4 years; range: 14 days to 15 years) undergoing primary OLT from January 1991 to June 1996. These children were divided into donor-recipient gender match (M; n=64) and nonmatch (NM; n=73) groups and then classified into female to female (FF; n=30), female to male (FM; n=29), male to female (MF; n=44), and male to male (MM; n=34) subgroups. RESULTS: The M group had better graft and patient survival rates at both 1- and 5-year follow-up compared with the NM group (P<0.01). Graft and patient survival rates were different among gender subgroups (P<0.04). Graft and patient survival rates in the FM group were poorer than in the MM subgroup at both 1 and 5 years (P<0.03, P<0.01). The FM group had a higher incidence of early complications than the MM (P<0.01) group, with 50% and 33% of graft losses, respectively, related to the complications. To minimize the influence of hormonal factors, we have analyzed separately the patients younger than 12 and 10 years who had similar findings. CONCLUSION: Graft and patient survival rates after pediatric OLT are worse in gender mismatch groups, particularly for male recipients of female organs. Early complications play a role in the decreased survival rates.

Mycobacterium tuberculosis infection in pediatric liver transplant recipients.

OBJECTIVES: To study the incidence, clinical presentation, management, complications and outcome of tuberculosis in pediatric liver transplant recipients. METHODS: A retrospective review of the medical records of children who underwent liver transplantation between 1991 and 1998. RESULTS: Mycobacterium tuberculosis infection occurred in 6 of 254 (2.4%) children undergoing liver transplantation between 1991 and 1998. Cough, pyrexia and poor appetite were common presentations; one-half had normal chest radiographs. The median time to confirmation of diagnosis was 8 months (range, 1 to 17 months). Tests contributing to diagnosis included: Ziehl-Neelsen (ZN) stain (2 patients), M. tuberculosis polymerase chain reaction (1 patient), Mantoux test (1 patient) and histopathology (4 patients). Family health screening was productive for 4 patients. Duration of treatment varied from 9 to 18 months. Isoniazid-induced hepatitis was observed in 2 patients but resolved with dose reduction. Two patients died while receiving treatment, one of Klebsiella spp. septicemia and the other of pulmonary hemorrhage. CONCLUSIONS: Tuberculosis after liver transplantation has a significant morbidity and mortality. Pretransplantation a personal and family history of tuberculosis must be sought, and screening of patients and their families should be considered. Standard regimens incorporating isoniazid and rifampin are effective, but regular monitoring of liver function is essential to detect drug-induced hepatotoxicity.

Ulcerative colitis in Zagreb, Yugoslavia: incidence and prevalence 1980-1989.

We present a ten-year incidence of ulcerative colitis in Zagreb, Yugoslavia. The study included both outpatients and inpatients regardless of the extent and severity of the disease. The mean annual incidence rate was 1.5 per 100,000 inhabitants for the period of 1 January 1980 through 31 December 1989. There was no increase in the incidence of ulcerative colitis during the study period. A prevalence rate estimate of 21.4 per 100,000 inhabitants was based on July 1985 official estimated population. The results confirm the low frequency of ulcerative colitis in central Europe.

Epidemiology of Crohn's disease in Zagreb, Yugoslavia: a ten-year prospective study.

A ten-year prospective study of Crohn's disease was carried out in Zagreb, Yugoslavia. It included both inpatients and outpatients regardless of the extent and severity of the disease. The mean annual incidence rate was 0.7 per 100,000 between 1 January 1980 and 31 December 1989. There was no increase in the incidence of Crohn's disease during the study period. The prevalence of Crohn's disease was 8.3 per 100,000 on 31 December 1989. The results confirm the low frequency of Crohn's disease in central and southern Europe.

Detection of hepatitis B virus pre-S1 and pre-S2 determinants in paraffin wax embedded liver tissue: importance of reagents used.

The presence of pre-S polypeptides in paraffin wax embedded liver sections from the biopsy specimens of 15 hepatitis B surface antigen (HBsAg) seropositive patients (five with chronic persistent hepatitis (CPH), four with chronic active hepatitis (CAH), four with cirrhosis and two "healthy" HBsAg carriers) was investigated using monoclonal antibodies directed to distinct epitopes on pre-S1 (18/7 and TO 606) and pre-S2 (5535 and Q 19/10). Pre-S1 was found in 13 cases when MA 18/7 was used but in only one specimen when TO 606 was used. Pre-S2 was detected in all the biopsy specimens with 5535 and in eight samples with Q 19/10. Mild enzymatic digestion annulled the staining of all monoclonal antibodies but Q 19/10. No association was observed between pre-S polypeptide expression and hepatitis B virus (HBV) replication or disease severity. Pre-S polypeptides can be detected readily in paraffin wax embedded material but the results obtained largely depend on the monoclonal antibodies used.

Non-myeloablative stem cell transplantation for congenital immunodeficiencies.

Allogeneic haematopoietic stem cell transplantation (HSCT) can be a highly successful treatment option for individuals with congenital immunodeficiency states. The strategy for HSCT is varied but in cases where there is preservation of residual T cell function, conditioning regimes have been used and have been based around a combination of busulphan and cyclophosphamide with or without serotherapy. In patients with coexisting organ damage this has resulted in significant morbidity and mortality. We have therefore used a low-intensity conditioning regime for transplantation in this group of immunodeficiency patients. Twenty-one patients with a variety of different immunodeficiencies were treated using the following conditioning regimes: (1) fludarabine/melphalan/ATG or Campath 1H (n=16), (2) fludarabine/cyclophosphamide/Campath 1H (n=1), (3) TBI/CyA/MMF (n=1), (4) fludarabine/melphalan/busulphan/ATG (n=3). In 13 cases matched (n=9) and 1 Ag mismatched (n=4) unrelated donors were used and in eight cases transplants from matched siblings (n=4), 1 Ag mismatched sibling (n=1), matched parent (n=1) and haploidentical parents (n=3) were performed. At a median follow-up of 13 months, 19 of 21 (90%) patients were still alive following the transplant procedure. Despite a T cell replete graft and the use of unrelated donor grafts in the majority of patients studied there was no evidence of significant organ disease. Immune reconstitution in terms of CD3+ and CD4+ T cell recovery and function was equivalent in comparison with a historical cohort. We believe that this low-intensity approach has significant implications for transplantation of individuals with immunodeficiency states with established organ disease.

Neonatal presentation of Caroli's disease.

A neonatal presentation of Caroli's disease with severe cardiac and progressive renal pathology is described. The availability of small paediatric endoscopes ensured early diagnosis. Despite aggressive medical management, the baby died with severe bleeding complications before potentially life saving multiple organ transplantation could take place.

[The role of and suitability of the occult fecal blood test in a preventive program for colorectal carcinoma]. / Uloga i prikladnost testiranja okultnoga fekalnog krvarenja u programu zastite od kolorektalnog karcinoma.

There are no final attitudes towards the necessity of the colorectal carcinoma screening in the population. The aim of this examination was to assess the motivation, applicability, sensibility and value of the occult faecal blood tests as the screening method in the colorectal carcinoma detection, as well as the analysis of the costs and the possibilities of testing within the regular health service. The testing of the occult faecal blood was offered to a random sample of 11.431 subjects. The tests were returned by 7.592 (81.9%) of the high-risk and by 1.690 (77.8%) of the control group testees. In the high-risk group (over 40 years of age) the positive test of the occult faecal blood was found in 1.09% of the examined patients and the colon carcinoma was established in 13 testees with the positive test (19.66%) or in 0.17% of the cases. The total costs per patient with a detected carcinoma were Din. 349.246. - what is 24.4% less than the price of a palliative operation. Colon adenoma was established in 16 testees of the high-risk group (0.21%). Colon adenoma and carcinoma were established in 34.94% of the testees with positive tests. Radical surgeries were made in 8 out of 10 operated testees. In the control group (20-40 years of age) two adenomas were established and no malignant disease. The test sensitivity was evaluated based on the colon carcinoma detection and it was 72.2% in Hemoccult-negative subjects up to two years after the testing.(ABSTRACT TRUNCATED AT 250 WORDS)

[Histamine levels in the blood in patients with malignant tumors]. / Razina histamina u krvi kod bolesnika s malignim tumorom.

The concentration of histamine in blood was determined in 22 patients with solid malignant tumors, 16 hospitalized non-cancer patients and 9 healthy subjects. Patients with cancer (mainly carcinomas of the breast and gastrointestinal tract) were divided into two groups: patients with resected primary tumor without known metastases (group I) and patients with present primary tumor with or without metastases (group II). In comparison with the healthy subjects (histamine concentration 69.0 +/- 6.03 ng.ml-1), cancer patients in both groups had significantly decreased levels of histamine in blood. Also, the concentration of histamine in patients with present tumor (group II; 40.1 +/- 3.48 ng.ml-1) vas significantly lower than in patients with resected primary tumor (49.9 +/- 3.14 ng.ml-1). Furthermore, hospitalized non-cancer patients had lower, but not statistically significant, concentration of histamine (59.7 +/- 6.13 ng.ml-1) than healthy subjects. These findings, together with similar data of other authors, suggest that decreased level of histamine in blood might be a good nonspecific marker for onset and progression of solid malignant tumors.

[Tissue carcinoembryonic antigen: a screening test for increased cell proliferation?]. / Tkivni karcinoembrionalni antigen (CEA): test probiranja pojacane stanicne proliferacije?

A relationship between the tissue and serum concentrations of carcinoembryonic antigen (CEA) as determined by the enzymoimmunoassay (EIA) was studied in 46 patients with colorectal carcinoma and 47 patients with gastric carcinoma. The values were then compared to those obtained in the control group of 64 healthy subjects. Serum CEA concentrations were measured in all of them, whereas tissue CEA concentration was determined in the rectal and gastric mucosa homogenates in 30 and 34 subjects, respectively. As expected, no differences were observed in the levels of serum CEA concentrations in either of the healthy subject subgroups. The serum CEA concentrations were found to be at the normal level of 2.5 ng/ml. In both subgroups of healthy subjects, the tissue CEA concentration was found to significantly differ, but the same was in colorectal and gastric carcinomas as compared to the normal rectal and gastric mucosa. When the process extent according to Dukes' classification in 22 patients with colorectal carcinoma operated on was compared to the relationship between the tissue and serum CEA concentrations, the serum CEA concentration of CEA was shown to depend on the tumor mass, regardless of the level of the specific tissue CEA concentration. Unusually high values of tissue CEA concentration, along with normal serum CEA concentration, were observed in 3 healthy subjects. A relationship between the tissue and serum CEA concentrations according to the degree of differentiation, studied in colorectal carcinomas, revealed significantly lower values of tissue CEA concentration in poorly differentiated carcinomas (P less than 0.01), whereas serum CEA concentrations did not show any such difference.

[Cigarette smoking and ulcerative colitis--is there a causal relationship?]. / Pusenje cigareta i ulcerozni kolitis--postoji li uzrocna veza?

The relation between cigarette smoking and ulcerative colitis was assessed in a case-control study of 235 cases of ulcerative colitis and 311 age- and sex-matched control subjects admitted to the hospital for conditions unrelated to smoking. Smoking habits and daily number of cigarettes smoked were analysed. We found significantly less number of smokers and more ex-smokers in the ulcerative colitis group. The intensity of smoking was equal in both groups. It was noted that pancolitis occurred more frequently in the ex-smokers group. The intensity of smoking did not influence the extension and clinical course of ulcerative colitis. For ulcerative colitis, the relative risk for nonsmokers was 7.4. The study revealed a positive correlation between nonsmoking and ulcerative colitis, higher incidence of pancolitis among ex-smokers and higher relative risk of ulcerative colitis for never-smokers. Various possible causes of influence of smoking on ulcerative colitis are discussed.

Hepatopathy of Mauriac syndrome: a retrospective review from a tertiary liver centre.

BACKGROUND: Mauriac syndrome is characterised by growth failure, cushingoid appearance and hepatomegaly which occurs in patients with insulin dependent diabetes and was first described shortly after the introduction of insulin as a treatment for the condition. OBJECTIVE: To describe the clinical features, histological findings and outcome of young people with glycogenic hepatopathy, the hepatic manifestation of Mauriac syndrome (MS). DESIGN: Retrospective cohort study. PATIENTS: Young people with glycogenic hepatopathy. SETTING: Tertiary paediatric hepatology unit. RESULTS: Thirty-one young people (16 M), median age of 15.1 years (IQR 14-16.2) presented within the study period. Median age of diagnosis of diabetes was 10 years (IQR 8-11). Median insulin requirement was 1.33 units/kg/day; median HbA1c was 96.7 mmol/mol (IQR 84.7-112.0). Growth was impaired: median height z-score was -1.01 (-1.73 to 0.4) and median body mass index (BMI) z-score was 0.28 (-0.12 to 0.67). Hepatomegaly was universal with splenomegaly in 16%. Transaminases were abnormal with a median aspartate aminotransferase (AST) of 76 IU/L and gamma glutamyltransferase of 71 IU/L. Liver biopsy was undertaken in 19 (61%). All showed enlarged hepatocytes with clear cytoplasm with glycogenated nuclei in 17. Steatosis was present in the majority. Inflammation was present in 8 (42%). Fibrosis was seen in 14 (73%) and was generally mild though 2 had bridging fibrosis. Megamitochondria were described in 7. Presence of megamitochondria correlated with AST elevation (p=0.026) and fibrosis on biopsy (p=0.007). At follow-up 17 children had normal or improved transaminases, in 13 there was no change. Transaminases followed the trend of the child's HbA1c. CONCLUSIONS: Despite modern insulin regimens and monitoring in children with type 1 diabetes, MS still exists. Significant steatosis, inflammation and fibrosis were all seen in liver biopsies.