Lovastatin therapy for cholesterol ester storage disease in two sisters

We administered lovastatin to two sisters, aged 4 and 17 years, who had cholesterol ester storage disease, an autosomal recessive disorder manifested by hypercholesterolemia and hypertriglyceridemia. The drug, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was taken orally for 6 months. Serum lipid concentrations were determined monthly. Computed tomography of the liver was performed before and during therapy to evaluate liver fat content. The younger sister had liver biopsies before and after 6 months of lovastatin therapy to assess hepatic cholesterol stores. Both patients had marked decreases in serum levels of cholesterol, triglycerides, and low-density lipoprotein-cholesterol; high-density lipoprotein-cholesterol levels increased. Computed tomography during treatment demonstrated a significant increase in linear attenuation, suggesting a decreased liver fat content. Liver tissue obtained 6 months after lovastatin therapy was initiated had 13% less esterified cholesterol than the liver sample obtained before treatment. We conclude that lovastatin may be effective in treating children with cholesterol ester storage disease.     

Impact of liver transplantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease

Congenital hepatic fibrosis (CHF) is an uncommon autosomal recessive malformation. It may be associated with extrahepatic manifestations such as polycystic kidney disease. The main consequence is portal hypertension and bleeding from varices. Despite liver transplantation as a therapeutic option for this patient, long-term impact of liver transplantation on renal functions of patients with autosomal recessive polycystic kidney disease with associated liver disease is not well known. In this study, we aimed to analyze the patient's renal function after liver transplantation by creatinine clearance, glomerular filtration rate, and renal resistive indexes. Between March 1997 and September 2002, three of 50 orthotopic liver transplantation (OLT) were performed because of CHF associated with ARPKD at Ege University Organ Transplantation and Research Center. Baseline immunosuppression consisted of prednisone and cyclosporine A (CSA). The mean follow-up of the patients was 2.1 yr. Blood urea and creatinine levels were decreased after operation in all patients and remained within the normal range at the sixth and 12th month, whereas the level of the third patient were increased at the 18th month. RRI values of patients were not found different at the sixth month whereas, RRI values of patients were decreased at the 12th month and remained unchanged at the 18th month of follow-up. During the study period hypertension developed in one patient at the 16th month and resolved with antihypertensive treatment and decreasing dosage of CSA. Kidney function has remained satisfactory in all of the patients despite the use of cyclosporine. OLT can provide good survival in patients with CHF associated with ARPKD.     

Pediatric liver transplantation from a living donor in mitochondrial disease: Good outcomes in DGUOK deficiency?

DGUOK deficiency is an autosomal recessive mitochondrial disorder characterized by hepatic and neurological manifestations. In patients with liver failure, the decision to perform LT can be difficult due to the likelihood of progressive neurological disease. We present a case of a 9‐month‐old boy who had DGUOK deficiency (E227K/R118H genotype) intact neurological status and liver failure. His MRI indicated extensive white matter changes, which created hesitation to perform LT. After a multidisciplinary evaluation, he underwent LT from a living donor at 11 months of age. Six years post‐transplant, he has had no significant complications and no progression of neurological symptoms. Our case supports that even in the presence of neurological MRI findings, but in the absence of significant neurological symptoms, LT represents a viable option in DGUOK‐deficient patients who have the E227K/R118H mutation combination along with liver failure.     

Liver involvement in Alpers disease

Alpers disease consists of diffuse cerebral degeneration manifested as developmental delay, seizures, vomiting, and progressive neuromuscular deterioration, with liver disease and death. We report the clinical course of the liver disease, histologic progression of the hepatic lesions, and etiologic investigations in five patients (four girls, three kinships). All had grown and developed normally until seen at 6 to 36 months of age (mean 20 months), with vomiting (n = 5), progressive hypotonia (n = 3), or seizures (n = 2). All had been given anticonvulsants, including valproic acid in three. Liver disease was noted at a mean age of 35 months (range 9 to 67 months), with hepatomegaly (two patients), abnormal hepatic synthetic function (three) or transaminase values (three), and cirrhosis in one. Patients survived for a mean of 4.6 weeks (range 1 to 8 weeks) after the identification of liver disease; all died of hepatic failure. Results of evaluation for infectious and metabolic causes of liver disease and causes of degenerative neuromuscular disease were negative in all patients. Premortem liver biopsy specimens (n = 3) demonstrated an early lesion consisting of lobular disarray, microvesicular steatosis, periportal acute and chronic inflammation, and individual hepatocyte necrosis. Autopsy findings (n = 5) consisted of macrovesicular steatosis, massive hepatocyte dropout, and proliferation of bile ductular elements, with almost complete replacement of hepatocytes by proliferating bile ductular elements in two patients. Brain showed characteristic neuronal degeneration. We conclude that Alpers disease can be a cause of rapidly progressive liver failure in early childhood. Although the cause of this autosomal recessive disease is not known, it does not appear to be related to peroxisomal dysfunction.     

Increased expression of transforming growth factor-beta1 and thrombospondin-1 in congenital hepatic fibrosis: possible role of the hepatic stellate cell

BACKGROUND: Congenital hepatic fibrosis is a rare disease characterized by portal tract fibrosis and biliary duct ectasia. It is associated with autosomal recessive polycystic kidney disease and rarely progresses to cirrhosis. The activated stellate cell has been implicated in the pathogenesis of alcohol- or inflammation-mediated cirrhosis through fibrogenic proteins such as transforming growth factor-beta1; however, the role of the stellate cell in pure, noninflammatory fibrosis is unknown. It has been hypothesized that fibrosis in congenital hepatic fibrosis may be caused by upregulation of transforming growth factor-beta1 and thrombospondin-1, and that the hepatic stellate cell may be the mediator of these proteins. METHODS: Human liver tissue samples from patients with congenital hepatic fibrosis (n = 9) and from normal patients (n = 3) were analyzed. Tissue homogenates from both groups were analyzed for transforming growth factor-beta1 protein and mRNA by Western blot analysis and in situ hybridization, respectively. Immunolocalization studies were performed in fixed tissue sections from both groups. Stellate cells were cultured from livers exhibiting congenital hepatic fibrosis and confirmed by desmin staining. The cells were cultured in serum-free medium for 48 hours, and media were collected and analyzed by Western blot analysis for thrombospondin-1 and transforming growth factor-beta1. RESULTS: Congenital hepatic fibrosis liver tissue homogenates had higher levels of thrombospondin-1 and transforming growth factor-beta1 protein than in normal livers. In congenital hepatic fibrosis tissue, transforming growth factor-beta1 was more highly expressed in the ectatic biliary epithelium and the perisinusoidal space, whereas thrombospondin-1 localized most intensely to the hepatocytes and spared the bile ducts. Congenital hepatic fibrosis-derived stellate cells secreted both thrombospondin-1 and transforming growth factor-beta1, in vitro. CONCLUSIONS: Transforming growth factor-beta1 and thrombospondin-1 may play a role in the pathogenesis of liver fibrosis in patients with congenital hepatic fibrosis. One potential source of these fibrogenic proteins is the hepatic stellate cell.     

A prospective evaluation of iron chelation therapy in children with severe beta-thalassemia. A six-year study

Sixteen patients (age range, 3 to 17 years) with transfusion-dependent beta-thalassemia major were studied prospectively, beginning at the onset of chelation therapy with deferoxamine (desferrioxamine). A liver biopsy specimen was obtained from each patient at the start of the study, and periodically thereafter. Liver histologic features, iron content, and iron excretion were assessed during the course of the study. Hepatic iron levels from liver biopsy specimens appeared to correlate well with serum ferritin levels in the younger less heavily iron-loaded patients; however, in patients with higher serum ferritin levels, hepatic iron appeared to reach a saturation level. Fourteen of the 16 patients showed a pattern of marbled fibrosis of the liver in their initial biopsy specimens. Follow-up biopsy specimens from nearly all of the patients showed a substantial reduction in iron concentration, but only two of seven patients showed improvement in the degree of hepatic fibrosis three to five years later. Patients less than 8 years old exhibited a normal pattern of linear growth until approximately the age of 10 years, followed by a progressive decrease to the 30th to 40th percentile. Two patients, aged 18 and 22 years, died of cardiac disease during the study. These findings suggest that chelation therapy in patients with transfusion-dependent thalassemia needs to be initiated at an early age, possibly before 3 years, if significant liver fibrosis and growth impairment are to be effectively prevented.     

Lafora disease: A progressive myoclonus epilepsy

Lafora disease is a rare inborn error of metabolism resulting in storage of a polyglucosan in tissues including the brain, skin and liver. Four children are described with progressive myoclonus epilepsy and intellectual deterioration in whom this diagnosis was made. In two the diagnosis was confirmed by the presence of periodic acid schiff (PAS) positive, diastase resistant, colloidal iron staining inclusion material in the liver when they were referred to a paediatric gastroenterologist with abnormal liver function tests. In one, the diagnosis was made from cerebellar biopsy, although on retrospective review the liver biopsy performed at this time was abnormal. In a fourth child, whose sibling was affected, histological diagnosis was confirmed by skin biopsy, although clinical and EEG findings had been highly suggestive for several years. The disease has autosomal recessive inheritance, is progressive and the prognosis is poor. Paediatricians should be aware of this diagnosis, which is often delayed, as early histological diagnosis allows prognostic and genetic counselling and optimal treatment. Although the diagnosis was made by liver or brain biopsy in three cases, skin biopsy offers a reliable, less invasive means of diagnosis.     

Progressive neuronal degeneration of childhood (Alpers syndrome) with hepatic cirrhosis

Four children, from two families, suffered from fatal degeneration of the cerebral grey matter. Their disease was characterised by intractable epilepsy, epilepsia partialis continua, progressive deterioration, and terminal hepatic dysfunction. EEG showed marked and distinctive slow wave abnormality, visual evoked responses were diminished, and cerebral atrophy was seen on CT scan. Pathological findings were of neuronal loss and hepatic cirrhosis. The combination of cerebral degeneration, hepatic disease and familial occurrence suggests an inborn error of metabolism with autosomal recessive inheritance. The features described are those of Alpers syndrome, especially the recently delineated subgroup with progressive neuronal degeneration and liver disease.     

Atomic Absorption Spectrometry in Wilson's Disease and Its Comparison with Other Laboratory Tests and Paraclinical Findings

Objective

Wilson''s disease (WD) is an autosomal recessive disease with genetic abnormality on chromosome 13 causing defect in copper metabolism and increased copper concentration in liver, central nervous system and other organs, which causes different clinical manifestations. The aim of this study was to determine the sensitivity of different clinical and paraclinical tests for diagnosis of Wilson''s disease.

Methods

Paraffin blocks of liver biopsy from 41 children suspicious of WD were collected. Hepatic copper concentrations were examined with atomic absorption spectrophotometry (Australian GBC, model: PAL 3000). Fifteen specimens had hepatic copper concentration (dry weight) more than 250μg/g. Clinical and laboratory data and histologic slides of liver biopsies of these 15 children were reviewed retrospectively. Liver tissue was examined for staging and grading of hepatic involvement and also stained with rubeonic acid method for copper.

Findings

Patients were 5-15 years old (mean age=9.3 years, standard deviation=2.6) with slight male predominance (9/15=60%). Five (33%) patients were 10 years old. Three (20%) of them were referred for icterus, 8 (54%) because of positive family history, 2 (13%) due to abdominal pain and 2 (13%) because of hepatosplenomegaly and ascites. Serum AST and ALT levels were elevated at the time of presentation in all patients. In liver biopsy, histological grade and stage was 0-8 and 0-6 respectively, 2 (13%) had cirrhosis, 1 (7%) had normal biopsy and 12 (80%) showed chronic hepatitis. Hepatic copper concentrations were between 250 and 1595 μg/g dry weight. The sensitivity of various tests were 85% for serum copper, 83% for serum ceruloplasmin, 53% for urinary copper excretion, 44% for presence of KF ring and 40% for rubeonic acid staining on liver biopsies.

Conclusion

None of the tests stated in the article were highly sensitive for diagnosis of WD, so we suggest that diagnosis should be based on combination of family history, physical examination and different tests.     

Liver disease in autosomal recessive polycystic kidney disease

Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD). PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation. Portal hypertension and biliary disease are the major liver problems seen in ARPKD. Complete blood counting, physical examination, ultrasonography and magnetic resonance (MR) cholangiography are indicated as screening procedures for hepatic disease in ARPKD. Medical and surgical interventions are potentially indicated for children with portal hypertension and/or biliary disease. A high index of suspicion for the diagnosis of cholangitis needs to be maintained in children with biliary disease. The implications of hepatic disease need to be considered in the decision-making regarding renal transplantation in ARPKD.     

Phosphorylase b kinase deficiency in a boy with glycogenosis affecting both liver and muscle

A boy with marked hepatomegaly and motor weakness was investigated for glycogen storage disease. Glycogen accumulation was demonstrated in both liver and muscle and there was a deficiency of phosphorylase b kinase activity. On the basis of biochemical findings, an autosomal recessive mode of inheritance was considered likely, rather than the more common X-linked variant, with primarily liver involvement.     

Caroli disease, bilateral diffuse cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas: a ciliopathy caused by a homozygous NPHP3 mutation

We report the rare association of Caroli disease (intrahepatic bile duct ectasia associated with congenital hepatic fibrosis), bilateral cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas in a female child. She presented with end-stage renal disease at the age of 1 month, followed by a rapidly progressing hepatic fibrosis and dilatation of the intrahepatic bile ducts, leading to secondary biliary cirrhosis and portal hypertension. Combined liver–kidney transplantation was performed at the age of 4 years, with excellent outcome. DNA analysis showed a NPHP3 (coding nephrocystin-3) homozygote mutation, confirming that this malformation complex is a ciliopathy. Conclusion: This rare association required an exceptional therapeutic approach: combined simultaneous orthotopic liver and kidney transplantation in a situs inversus recipient. The long-term follow-up was excellent with a very good evolution of the renal and hepatic grafts and normalization of growth and weight. This malformation complex has an autosomal recessive inheritance with a 25% recurrence risk in each pregnancy.     

3例糖原贮积症Ⅱ型患儿的临床特点及GAA基因突变分析

糖原贮积症Ⅱ型(GSDⅡ)是一种主要由酸性α-葡萄糖苷酶(GAA)基因突变引起的常染色体隐性遗传病,主要累及心脏、骨骼肌等脏器。本文报道3例经GAA基因分析确诊的GSDⅡ患儿的临床特点和基因突变结果,1例为婴儿型,年龄为4个月,患儿表现为体重不增,呼吸困难,肌张力低,ALT、CK升高,心脏彩超示肥厚型心肌病。2例为晚发型,年龄分别为8岁、13岁,晚发型患儿均表现为持续肝酶升高,其中1例患儿伴反复呼吸道感染,肺功能示限制性通气障碍;另1例患儿伴肌酶升高明显,而肌电图正常。外周血GAA基因检查结果显示3例患儿中共检测出6种致病突变,其中c.2738CT、c.568CT为未见报道的新突变。外周血GAA基因检测是有效的诊断该疾病的方法。     

Liver transplantation for glycogen storage disease types I, III, and IV

Glycogen storage disease (GSD) types I, III, and IV can be associated with severe liver disease. The possible development of hepatocellular carcinoma and/or hepatic failure make these GSDs potential candidates for liver transplantation. Early diagnosis and initiation of effective dietary therapy have dramatically improved the outcome of GSD type I by reducing the incidence of liver adenoma and renal insufficiency. Nine type I and 3 type III patients have received liver transplants because of poor metabolic control, multiple liver adenomas, or progressive liver failure. Metabolic abnormalities were corrected in all GSD type I and type III patients, while catch-up growth was reported only in two patients. Whether liver transplantation results in reversal and/or prevention of renal disease remains unclear. Neutropenia persisted in both GSDIb patients post liver transplantation necessitating continuous granulocyte colony stimulating factor treatment. Thirteen GSD type IV patients were liver transplanted because of progressive liver cirrhosis and failure. All but one patient have not had neuromuscular or cardiac complications during follow-up periods for as long as 13 years. Four have died within a week and 5 years after transplantation. Caution should be taken in selecting GSD type IV candidates for liver transplantation because of the variable phenotype, which may include life-limiting extrahepatic manifestations. It remains to be evaluated, whether a genotype-phenotype correlation exists for GSD type IV, which may aid in the decision making. Conclusion Liver transplantation should be considered for patients with glycogen storage disease who have developed liver malignancy or hepatic failure, and for type IV patients with the classical and progressive hepatic form.     

Hepatobiliary sonography in cystic fibrosis

Real-time abdominal sonograms of 27 pediatric patients with cystic fibrosis were reviewed to determine the frequency of hepatobiliary abnormalities and their variation with patient age. Attention was paid to hepatic echotexture and gallbladder size and contents. Seventeen patients (63%) had abnormal livers appearing as diffuse hyperechogenicity with loss of visualization of periportal echoes in 5 of 17 patients (29%), periportal hyperechogenicity in 9 of 17 (53%) and heterogeneity in 3 of 17 (17%). Gallbladder abnormalities, including a small gallbladder and sludge, were found in 9 patients (33%). Our findings show that altered hepatic echotexture is quite common in children with cystic fibrosis. Younger children tend to have diffusely hyperechoic livers, while older children often demonstrate periportal hyperechogeneity or diffuse hepatic heterogeneity.     

Arthrogryposis, renal tubular dysfunction, cholestasis (ARC) syndrome: case report and review of the literature

The ARC-syndrome is a rare disease with the obligatory symptoms arthrogryposis, renal tubular dysfunction and cholestasis. Optional further symptoms like ichthyosis, diarrhea, central nervous system defects and recurrent infections have been reported. The ARC-syndrome was first reported by Lutz-Richner and Landolt in 1973. The pathophysiology is still unknown, an autosomal recessive inheritance is postulated. Patients rarely exceed an age of six month. We report a boy of consanguineous Turkish parents who suffered from congenital deformities of the lower extremities, a metabolic acidosis and failure to thrive. In the sequel he developed a renal Fanconi syndrome and cholestasis. Histology of liver and muscle biopsy specimen showed the typical findings of the disease with giant cell hepatitis and neurogenous muscle atrophy. His condition could be stabilized and he increased in weight by substituting fluid, electrolytes, buffer and parenteral nutrition. Total enteral nutrition of the 280 ml/kg/d he required failed even by nasogastric tube and percutaneous endoscopic gastrostomy. Additional fluid substitution by central venous catheter remained necessary. At the age of 7 month he died.     

Anti-CD52 antibody, alemtuzumab, binds to Langerhans cells in Langerhans cell histiocytosis

BACKGROUND: The humanized anti-CD52 monoclonal antibody, alemtuzumab (or Campath-1H), has been shown to potently deplete lymphocytes in human patients. It has been used to successfully treat graft versus host disease and chronic lymphocytic leukemia (CLL). CD52 is expressed on normal lymphocytes, monocytes, and some dendritic cell subsets. However, normal Langerhans cells (LC's) in the skin do not bind alemtuzumab. We sought to determine whether the pathologic LC's of Langerhans cell histiocytosis (LCH) express CD52 and thus could be targeted by this antibody. METHODS: Immunohistochemistry was performed on both frozen and fixed/paraffin-embedded tissue specimens using either Campath-1G (the parental rat isotype) or Campath-1H (the humanized version of Campath in clinical use). RESULTS: Both Campath-1H and Campath-1G were found to bind to the pathologic LC's in LCH, but not the normal LC's of skin. Specific staining was demonstrated in all (13 of 13) LCH specimens examined, though staining was somewhat variable among specimens, and tended to be weaker in paraffin-embedded specimens. CONCLUSIONS: Expression of CD52 by the pathologic LC's seen in LCH suggests that alemtuzumab may represent a new, targeted therapy for this disease. Such therapy is particularly needed for patients with refractory, high-risk disease. Further investigation of the possible clinical use of this antibody in these patients is warranted.     

Meckel syndrome with Caroli disease and choledochal cysts

Meckel syndrome is a lethal autosomal recessive disorder characterized by the triad of cystic renal dysplasia, occipital encephalocele, or other anomaly of the central nervous system and post-axial polydactyly. Malformation of the ductal plate is an integral component of Meckel syndrome. Ductal plate malformations include congenital hepatic fibrosis, biliary hamartoma, autosomal dominant polycystic liver disease, Caroli disease, and choledochal cyst. The occurrence of cystic hepatic disease, Caroli disease, and choledochal cyst have not been highlighted. This is a report of a 26-week fetus with features of Meckel syndrome, Caroli disease, and choledochal cyst.     

Morphometric Studies of Cystic and Tubulointerstitial Kidney Diseases with Hepatic Fibrosis in Children

Portal tract fibrosis with biliary ductular enlargement or proliferation occurs in a number of genetic diseases that have cystic or tubulointerstitial renal lesions. These include some with renal cystic disease such as autosomal recessive diseases (e.g., infantile polycystic disease, juvenile polycystic disease, and Meckel's syndrome), autosomal dominant diseases (e.g., adult polycystic disease), and, rarely, tuberose sclerosis and dominant glomerulocystic disease. Portal tract fibrosis with biliary enlargement and proliferation occurs also with tubulointerstitial kidney diseases. These probably include at least three disorders in the category nephronophthisis-congenital hepatic fibrosis (one autosomal recessive disease and two either autosomal or X-linked recessive diseases) plus Jeune's syndrome (the tubulointerstitial diseases Fanconi's familial nephronophthisis and anti-tubular membrane antibody disease do not regularly cause hepatic fibrosis). Morphometric data on ratios of bile ductules to connective tissue in hepatic portal tracts show high values for infantile polycystic disease (mean, 0.616) compared to lower values for juvenile polycystic disease (mean, 0.286). That the cystic renal lesions of the first two diseases differ in type and time course is known. Similar data on ratios of glomeruli plus tubules to connective tissue in renal cortices and of tubules to connective tissue in outer medullary zones of kidneys, respectively, are as follows: for Fanconi's nephronophthisis, 0.445 and 0.197; for anti-tubular basement membrane antibody disease, 0.585 and 0.164; and for the three types of nephronophthisis-congenital hepatic fibrosis studied, 0.668 and 0.446, 1.39 and 0.921, and 1.18 and 0.12. These data support clinical impressions that the category nephrophthisis-congenital hepatic fibrosis includes more than one disease entity.     

Morphometric studies of cystic and tubulointerstitial kidney diseases with hepatic fibrosis in children

Portal tract fibrosis with biliary ductular enlargement or proliferation occurs in a number of genetic diseases that have cystic or tubulointerstitial renal lesions. These include some with renal cystic disease such as autosomal recessive diseases (e.g., infantile polycystic disease, juvenile polycystic disease, and Meckel's syndrome), autosomal dominant diseases (e.g., adult polycystic disease) and, rarely, tuberose sclerosis and dominant glomerulocystic disease. Portal tract fibrosis with biliary enlargement and proliferation occurs also with tubulointerstitial kidney diseases. These probably include at least three disorders in the category nephronophthisis-congenital hepatic fibrosis (one autosomal recessive disease and two either autosomal or X-linked recessive diseases) plus Jeune's syndrome (the tubulointerstitial diseases Fanconi's familial nephronophthisis and anti-tubular membrane antibody disease do not regularly cause hepatic fibrosis). Morphometric data on ratios of bile ductules to connective tissue in hepatic portal tracts show high values for infantile polycystic disease (mean, 0.616) compared to lower values for juvenile polycystic disease (mean, 0.286). That the cystic renal lesions of the first two diseases differ in type and time course is known. Similar data on ratios of glomeruli plus tubules to connective tissue in renal cortices and of tubules to connective tissue in outer medullary zones of kidneys, respectively, are as follows: for Fanconi's nephronophthisis, 0.445 and 0.197; for anti-tubular basement membrane antibody disease, 0.585 and 0.164; and for the three types of nephronophthisis-congenital hepatic fibrosis studied, 0.668 and 0.446, 1.39 and 0.921, and 1.18 and 0.12. These data support clinical impressions that the category nephrophthisis-congenital hepatic fibrosis includes more than one disease entity.