Serum levels of carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen and laminin P1 in Duchenne muscular dystrophy

The striking proliferation of connective tissue in Duchenne muscular dystrophy is attributed, besides other components of the extracellular matrix, to an increase of endomysial and perimysial type III and type I collagen. We investigated if muscle fibrosis correlates to an increased serum concentration of procollagen I or HI. Therefore, we measured the serum levels of carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen and laminin P1 in 20 boys with progressive muscular dystrophy (16 definite Duchenne muscular dystrophy, 2 suspected of Duchenne muscular dystrophy, 2 Becker muscular dystrophy). In contrast to collagen I and III the expression of laminin in the basement membrane is known to be normal in Duchenne muscular dystrophy. There was no significant alteration of serum concentration of procollagen ni N-peptide, procollagen I C-peptide and laminin PI in boys with Duchenne muscular dystrophy. Measuring these parameters is not useful for investigating the extent of muscle fibrosis or for monitoring the effect of therapeutic trials such as steroid treatment.     

Collagen peptides in osteogenesis imperfecta, idiopathic juvenile osteoporosis and Ehlers–Danlos syndrome

We evaluated the potential of the carboxy-terminal propeptide of type I procollagen (PICP), the carboxy-terminal telopeptide of collagen I (ICTP), and the amino-terminal propeptide of type III procollagen (PIIINP) to differentiate osteogenesis imperfecta (OI) from Ehlers Danlos syndrome (EDS) and idiopathic juvenile osteoporosis (IJO) in paediatric patients. Markedly decreased serum concentrations of PICP were found in type I OI, while in IJO they were much less diminished, and in EDS they were near to normal. In type III and IV OI, the serum PICP level was lowered in prepubertal patients, whereas at puberty it was comparable to that in controls. Serum ICTP and PIIINP levels in patients with OI did not differ significantly from the levels in EDS and IJO. Measurements of scrum PICP levels seem to be useful in discriminating OI from EDS and IJO in prepubertal children. In pubertal children, however, they lose their diagnostic power.     

Serum concentrations of extracellular matrix components: novel markers of metabolic control and hepatic pathology in glycogen storage disease?

Laminin, hyaluronic acid (HA), procollagen III amino-terminal propeptide (PIIINP), and procollagen I carboxy-terminal propeptide (PICP) concentrations were measured by radioimmunoassay or radiometric assay in sera from 21 patients with glycogen storage disease (GSD). Laminin was increased in 16 of 29 samples from the six children with GSD I, 25/43 from the seven with GSD III, and 3/19 from the eight with GSD IX; laminin correlated with serum aspartate aminotransferase and gamma-glutamyltransferase but not with serum triglycerides, cholesterol, lactate, or urate. HA was increased in 20% of samples from GSD I, 58% from GSD III, and in none from GSD IX; HA correlated with serum lactate and urate but not with liver function tests, serum cholesterol, or triglycerides. Serum PIIINP was increased in only eight samples and PICP in only one; children with poor linear growth had low PIIINP and PICP. Immunostaining studies of nine liver biopsies taken at diagnosis showed increased laminin and PIIINP staining in portal tracts, fibrous septa, and around sinusoids in periportal regions; children with a greater degree of immunostaining did not always show significantly higher values of serum laminin or PIIINP. We speculate that raised serum laminin may reflect fibrogenesis (but not necessarily established fibrosis) in response to tissue damage in GSD, raised HA may reflect disturbed sinusoidal endothelial cell function, and low PIIINP and PICP impaired somatic growth rather than intrahepatic pathology.     

Prolylhydroxylase and procollagen type III in long-term survivors of acute lymphoblastic leukemia (ALL): a biochemical approach to HCV-related liver disease

BACKGROUND: We examined two proteins, prolylhydroxylase (hPH) and procollagen type III (PIIIP), as possible non-invasive HCV-related markers of liver disease. The purpose of this study was to assess whether the measurement of these proteins could serve to monitor HCV related liver damage in acute lymphoblastic leukaemia (ALL) patients. PROCEDURE: A total of 34 ALL patients, 24 HCV-seropositive and 10 HCV-seronegative, who had had increased transaminase values (ALT) for almost 6 months were studied. Serum hPH concentrations were determined by an immuno-enzymatic assay kit. PIIIP was assayed by the radioimmunoassay method. RESULTS: Both hPH and PIIIP were increased in ALL patients with chronic hepatitis C. Serum hPH levels were significantly elevated in those with chronic hepatitis C with either normal or high transaminases when compared to those who never were HCV seropositive. The sensitivity and specificity of these protein measurements to evaluate hepatic fibrosis were not supported by histologic confirmation because only 6 out of 12 patients with chronic hepatitis had a liver biopsy. CONCLUSIONS: Our study suggests that PIIIP and hPH values are significantly higher in ALL patients with chronic HCV with either normal or high transaminases. This might suggest that the liver damage is more marked in patients with chronic hepatitis and that the liver damage is related to the HCV rather than chemotherapy. Future studies correlating histologic findings with the serum biochemical markers are required to establish the sensitivity and specificity of hPH and PIIIP in predicting hepatic fibrosis and to confirm this association.     

Enzyme defect in a case of tyrosinemia type I, acute form

We determined the activities of tyrosine aminotransferase (TAT, EC 2.6.1.5), p-hydroxyphenylpyruvate oxidase (p- HPPA oxidase, EC 1.14.2.2) and fumarylacetoacetate fumarylhydrolase ( FAH , EC 3.7.12) in cytosol of the liver and kidney tissues obtained at autopsy from a case of hereditary tyrosinemia type I. Values were compared with those from a control group of autopsied tissues from three adults and six children, who had died of other causes. In tyrosinemia, these three hepatic enzyme activities were all decreased: TAT showed approximately 35%, p- HPPA oxidase 11%, and FAH 60% of the corresponding control values. On the other hand, kidney enzymes in tyrosinemia revealed that FAH was most significantly decreased to approximately 14% of the control activity. Km values for substrate--determined for p- HPPA oxidase and FAH --were not different between the patient and controls, suggesting no altered properties of these enzymes. We conclude that in the present case of hereditary tyrosinemia type I, the activities of p- HPPA oxidase in liver and FAH in kidney were most strikingly affected. This fact may in part explain the deteriorated metabolism of tyrosine observed in this patient.     

A fetal case of transient abnormal myelopoiesis with severe liver failure in Down syndrome: prognostic value of serum markers

The authors recently encountered a lethal case of Down syndrome with transient abnormal myelopoiesis (TAM). Although the peripheral white blood cell count and blast cells had improved without specific treatment, the patient died of severe coagulopathy due to liver fibrosis when he was 5 years old. The prognosis of TAM with liver fibrosis was poor. The patient had high levels of N-terminal peptide of III procollagen, type IV collagen, and hyaluronic acid. These serum makers are noninvasive indicators of liver fibrosis and may be useful as prognostic indicators of TAM in Down syndrome.     

Rapid improvement in the renal tubular dysfunction associated with tyrosinemia following hepatic replacement.

The postoperative management of patients with hereditary tyrosinemia type I (McKusick 27670) following liver transplantation is often complicated by the renal tubular dysfunction associated with this disease. To characterize better the temporal course of the improvement in renal excretory activity following hepatic replacement, renal tubular function and metabolite excretion were studied in a 4-year-old girl with hereditary tyrosinemia during the immediate post-transplantation course. Tubular reabsorption of bicarbonate and phosphate were normal 5 days following transplantation, in contrast to glucosuria, hyperaminoaciduria, and tyrosyluria, which persisted for approximately 3 weeks. After hepatic replacement, serum amino acid concentrations returned to normal and succinylacetone was no longer detected in the urine. This is the third tyrosinemia patient reported to achieve complete resolution of urinary abnormalities following transplantation, and the only patient in whom renal tubular function was formally assessed within the first postoperative week.     

Favorable outcome of treatment with NTBC of acute liver insufficiency disclosing hereditary tyrosinemia type I]

BACKGROUND: Hereditary tyrosinemia type I is a disease with a severe prognosis. Main causes of death are acute liver failure, neurologic crises and hepatocarcinoma. NTBC, which acts as an inhibitor of the 4-hydroxyphenylpyruvate dioxygenase, prevents the formation of toxic metabolites involved in hepatic, renal and neurologic lesions. CASE REPORTS: Results of NTBC therapy used in three infants with type I tyrosinemia who presented with acute liver failure are reported. The diagnosis relied on the finding of high plasmatic levels of tyrosine and methionine, and abnormal urinary excretion of succinyl acetone and delta aminolevulinic acid. Treatment with NTBC was initiated within 2 to 8 days from onset of symptoms. Signs of liver failure resolved after 3 weeks therapy. After 12 to 39 months of follow-up, outcome remains favorable. CONCLUSION: The results reported here highlight the efficiency of NTBC in type I tyrosinemia with early acute onset. However, the long term outcome needs to be determined with regards to prevention of hepatocarcinoma and toxicity of the drug.     

The insulin-like growth factor axis and collagen turnover during prednisolone treatment.

Serum concentrations of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3), the carboxyterminal propeptide of type I collagen (PICP), the carboxyterminal pyridinoline crosslinked telopeptide of type I collagen (ICTP), and the aminoterminal propeptide of type III procollagen (PIIINP) were studied in 10 prepubertal children with asthma (mean age 9.0 years). The children were treated with 2.5 and 5.0 mg/day prednisolone in a randomised double blind crossover trial with run in, treatment, and washout periods of two weeks. No statistically significant effects on serum concentrations of IGF-I and IGFBP-3 were found. Dose related reductions of PICP, ICTP, and PIIINP were observed: the mean (SEM) reduction in PICP was 33.4 (26.3) and 68.4 (20.6) micrograms/l, in ICTP 2.5 (0.5) and 2.9 (0.6) micrograms/l, and in PIIINP 2.1 (0.7) and 3.1 (1.8) micrograms/l during the 2.5 and 5.0 mg prednisolone periods respectively. Short term treatment with low daily doses of prednisolone is associated with suppression of serum markers of type I and III collagen turnover in children with asthma. Intermediate and long term effects remain to be studied.     

Early liver transplantation is indicated for tyrosinemia type I

Liver transplantation is now accepted as the treatment of choice for tyrosinemia type I (hereditary tyrosinemia). In an effort to determine whether any factors in these patients would aid in predicting optimal timing of the transplant procedure, we evaluated several clinical, biochemical, and radiographic parameters in five successive patients undergoing liver transplant for tyrosinemia type I at the University of Minnesota. All five patients evidenced prolonged periods of clinical and metabolic stability with dietary therapy and four of five remained stable at the time of evaluation for transplantation. Nevertheless, all five suffered significant and unexpected complications of tyrosinemia prior to the time of liver transplant. Four developed renal stones, two were in liver failure, and one developed a neurologic crisis that left him completely paralyzed. Hepatocellular carcinoma was found in one of the five at transplant. We could identify no clinical, biochemical, or radiographic study that was predictive of the likelihood of significant complications of the disorder. Survival from the transplant procedure itself was 100%. The inability to predict or prevent significant complications of tyrosinemia and the favorable outcome from transplantation lead us to recommend liver transplant for all patients with tyrosinemia type I by 12 months of age.     

The insulin–like growth factor axis and collagen turnover in asthmatic children treated with inhaled budesonide

Serum concentrations of growth hormone–dependent insulin–like growth factor I (IGF–I) and insulinlike growth factor binding protein–3 (IGFBP–3), the carboxy terminal propeptide of type I procollagen (PICP), the carboxy terminal pyridinoline cross–linked telopeptide of type I collagen (ICTP) and the amino terminal propeptide of type III procollagen (PIIINP) were studied in 14 prepubertal children with asthma (mean age 9.7 years) during treatment with inhaled budesonide. The study design was a randomized, crossover trial with two double–blind treatment periods (200 and 800 μg) and one open, non–randomized treatment period (400 μg ). All periods were 18 days'duration. Budesonide treatment was associated with a dose–related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included (p < 0.01; z =–2.7) and when it was excluded from the calculations (p < 0.01; z =–2.6), indicating reduced synthesis of type III collagen. A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations (p = 0.05; z =–1.9). No other statistically significant variations were seen.     

复方甘草酸苷片治疗儿童非酒精性脂肪性肝病疗效观察

目的探讨复方甘草酸苷片治疗儿童非酒精性脂肪性肝病的临床疗效。方法将2014年6月至2016年5月就诊的65例非酒精性脂肪性肝病患儿随机分为复方甘草酸苷片治疗组(n=33)和护肝片对照治疗组(n=32),分别予以口服复方甘草酸苷片和护肝片治疗24周。两组患儿均于治疗前后检测血清丙氨酶氨基转移酶(ALT)、γ-谷氨酰转肽酶(γ-GT)、透明质酸(HA)、Ⅲ型前胶原(PCⅢ)、Ⅳ型胶原(CⅣ)和层黏连蛋白(LN)水平。结果复方甘草酸苷片组和护肝片组治疗总有效率分别为85%和50%,两组比较差异有统计学意义(P0.05);两组患儿血清ALT水平治疗后较治疗前均显著下降(P0.05),但复方甘草酸苷片组较护肝片组下降更明显(P0.01);复方甘草酸苷片组治疗后血清γ-GT水平以及肝纤维化四项指标(HA、PCⅢ、CⅣ、LN)水平较治疗前均得到明显改善(P0.05),而护肝片组上述各指标水平较治疗前均无显著变化(P0.05)。结论复方甘草酸苷片可有效改善非酒精性脂肪性肝病患儿的肝功能,并能降低肝纤维化血清学指标水平;其疗效优于护肝片治疗。     

Tyrosinemia type I: A clinico-laboratory case report

Progressive hepatocellular dysfunction in a neonate, resulting in elevated serum α-fetoprotein together with raised blood levels of tyrosine and methionine, a generalized amino aciduria and the absence of urinary δ-aminolevulinic acid and succinylacetone, suggests a diagnosis of tyrosinemia type Ib. Classical tyrosinemia type I arises from a deficiency of fumarylacetoacetate hydrolase while the variant tyrosinemia type Ib results from a deficiency of maleylacetoacetate isomerase.     

Serum concentrations of procollagen I C-terminal propeptide,osteocalcin and insulin-like growth factor-I in patients with non-lethal osteogenesis irnperfecta

Serum concentrations of procollagen I C-terminal propeptide (PICP) were studied in 74 patients with various forms of non-lethal osteogenesis imperfecta and 27 unaffected family members. Using the standard deviation (SD) score, PICP concentrations were found to be ≤— 1 SD in 16%, between — 1 and —2 SD in 26% and ≤— 2 SD in 58% of the patients with osteogenesis imperfecta compared to healthy controls. PICP values were lowest in osteogenesis imperfecta type I (- 2.4 ± 0.4 SD, n= 37) followed by type III (-1.9 ± 0.5 SD, n = 13) and type IV (- 1.3 ± 0.7 SD, n= 20). Four patients with osteogenesis imperfecta with an atypical clinical course had normal or even elevated levels which may indicate heterogeneity in the underlying primary defects. In osteogenesis imperfecta type I, PICP concentrations proved to be a helpful serum marker for pedigree screening. Osteocalcin was high in 25 of 28 patients with osteogenesis imperfecta in the first decade but only in 1 of 18 older patients. Insulin-like growth factor-I was within the normal range in 53 cases of osteogenesis imperfecta, decreased in 2 and elevated in 3 patients. We conclude that PICP concentration is a useful parameter in the clinical management of osteogenesis imperfecta, including the assessment of future therapeutic interventions.     

Beneficial effect of a traditional herbal medicine (inchin-ko-to) in postoperative biliary atresia patients

 Inchin-ko-to (ICKT) prevents Fas-mediated liver injury. This study evaluates the effect of ICKT on conventional markers of liver function (LF) and liver fibrosis in 18 postoperative biliary atresia (BA) patients aged 3 to 23 years with elevated glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), γ-glutamyl transpeptidase (γGTP) but normal serum total bilirubin (T-Bil) levels. ICKT (0.15 g/kg per day) was administered orally for 1 year. Serum GOT, GPT, γGTP, total bile acids (TBA), and T-Bil as markers of LF and hyaluronic acid (HA), prolyl hydroxylase (PH), procollagen III peptide (PIIIP), and type IV collagen as markers of liver fibrosis were measured before and after treatment in each patient and compared statistically. All patients tolerated ICKT well, and there were no side effects. The percentage of subjects who improved after ICKT was 45% for serum GOT, 72% for GPT, 72% for γGTP, 72% for TBA, 67% for HA, 40% for PH, 50% for PIIIP, and 23% for type IV collagen. Changes in the mean values of all serum markers were statistically significant (P < 0.01). It is concluded that long-term administration of ICKT in postoperative BA patients improves liver status as assessed by markers of LF and fibrosis. Accepted: 22 September 2000     

Diagnosis and treatment of hereditary tyrosinemia in Japan

Hereditary tyrosinemia is an autosomal recessive inherited disease that manifests as three types (types I–III). We conducted a nationwide survey of this disease in Japan, and here review the results in relation to prevalence, clinical characteristics, and treatment and diagnosis. A definitive diagnosis of tyrosinemia type I is difficult to obtain based only on blood tyrosine level. Detection of succinylacetone using dried blood spots or urinary organic acid analysis, however, is useful for diagnosis. In tyrosinemia type I, dietary therapy and nitisinone (Orfandin®) are effective. Prognosis is greatly affected by the complications of liver cancer and hypophosphatemic rickets; even patients that are treated early with nitisinone may develop liver cancer. Long‐term survival can be expected in type I if nitisinone therapy is effective. Prognosis in types II and III is relatively good.     

Serum concentrations of the type I and III procollagen propeptides as biochemical markers of growth velocity in healthy infants and children and in children with growth disorders

The reproducibility and specificity of a new, rapid, simple RIA for measuring the concentration of the soluble carboxypropeptide of type I procollagen (PICP) in serum was confirmed. Serum PICP was determined in 442 healthy Caucasian subjects ranging in age from 3 wk to 18 y. Highest PICP values (mean +/- SD: 2200 +/- 350 micrograms/L) occurred in infants less than 3 mo of age, falling by 70% at 2 y and by an additional 10% at 4 y. There was no significant change in serum PICP between 4 and 16 y of age (330 +/- 130 micrograms/L), but a decrease to adult levels of less than 160 micrograms/L occurred by 18 y. In 76 children with growth disorders, serum PICP was related to linear growth velocity (p less than 0.001), although there were no significant differences in PICP among the 38 children with growth hormone insufficiency, the 21 short children with no endocrinologic abnormality, or the 17 tall children. All 15 prepubertal children treated with growth hormone for 3 mo showed significant increases in both growth velocity and serum PICP, with a significant relationship (p less than 0.01) between the degree of increases. The rise in serum PICP at 3 mo (but not baseline PICP values) predicted the increase in growth velocity after 1 y of treatment. Similar changes were observed in the concentration of the aminopropeptide of type III procollagen, except that serum aminopropeptide of type III procollagen showed a definite increase during puberty and a wider spread of values in growth disorders. We conclude that measuring serum PICP by the new, reproducible assay reflects height velocity in prepubertal children and may be a useful biochemical means of monitoring growth rates.     

Chromosomal instability in hereditary tyrosinemia type I

Autopsy of a 4-year-old girl with hereditary tyrosinemia type I revealed a hepatocellular carcinoma in addition to cirrhosis and renal tubular dysplasia. Cytogenetic studies performed on a skin fibroblast culture demonstrated greatly increased chromosome breakage, which affected 71% of the cells. This suggests that the development of hepatoma, which is frequent in this syndrome, and the presence of dysplastic changes of hepatocytes in nontumorous liver are related to genetic instability caused by accumulation of intermediates of tyrosine catabolism, which are natural alkylating agents (e.g., maleylacetoacetate and fumarylacetoacetate). The other microscopic structural changes seen, such as renal tubular atypia, pancreatic islet cell hyperplasia, and focal necrosis of cortical neurons, may also be partly due to DNA damage caused by the accumulation of abnormal metabolites produced in patients with type 1 tyrosinemia.     

Biochemical bone markers in the assessment and pamidronate treatment of children and adolescents with osteogenesis imperfecta

Aim: To assess the role of biochemical bone markers in classification of children with osteogenesis imperfecta (OI), their possible association with vertebral compression fractures in milder forms of OI and their role in monitoring of intravenous pamidronate (APD) treatment. Methods: Serum total alkaline phosphatase (ALP), bone ALP isoforms (in a subgroup), osteocalcin, type I procollagen carboxy‐terminal propeptide, carboxy‐terminal telopeptide of type I collagen, and urine deoxypyridinoline (DPD) were measured in a cross‐sectional study of 130 untreated individuals, 0.25–20.9 years (median 6.7), with OI types I, III and IV. Of those, sixty‐nine were also assessed longitudinally during monthly APD treatment. Bone mineral density (BMD) was measured by dual‐energy X‐ray absorptiometry. Results: Significant differences in bone markers, however not sufficient for individual clinical use, were found in the larger untreated group but not between subgroups with or without vertebral compressions. All bone markers decreased during treatment for 1.0–12.5 years, but with different relative amounts. Changes were not correlated to the improvement in BMD, mobility or pain. Conclusion: Bone markers are, despite significant differences, not useful for the classification of OI type in the individual child and are not associated with vertebral compressions. Serum ALP and urinary DPD are sensitive in monitoring bisphosphonate treatment.     

Bone Turnover and Growth during and after Chemotherapy in Children with Solid Tumors

Children who are treated for malignancy have been shown to have decreased bone mineral density. We investigated the effect of serial courses of chemotherapy on growth and bone turnover in children with solid tumors. We measured height, weight, and lower leg length (LLL; n = 10) and markers of bone formation [bone alkaline phosphatase (BALP) and C-terminal propeptide of type I collagen (P1CP)], bone resorption [C terminal telopeptide of type I collagen (1CTP)], soft tissue collagen turnover [N-terminal propeptide of type III procollagen (P3NP)], and the GH axis [IGF1 and its binding proteins (IGFBP3 and IGFBP2)] before and after each course (n = 25) and on completion of treatment (n = 12). Height SD score decreased during treatment (p < 0.01) and increased to pretreatment levels at 3 mo off treatment (p < 0.05). LLL growth increased off treatment (p < 0.01). At diagnosis, BALP, PICP, and IGF1 SD score were low compared with age- and sex-matched reference groups (p < 0.001, p < 0.001, and p < 0.002, respectively) and IGFBP2 was elevated (p < 0.001). During treatment, P1CP, 1CTP, and P3NP showed a cyclical pattern decreasing after each course (p < 0.001) and increasing before the next course (p < 0.001). Precourse levels of BALP, P1CP, 1CTP, P3NP, IGF1, and IGFBP3 showed an upward trend during treatment. BALP remained suppressed throughout treatment (p < 0.001). Intense courses of treatment for solid tumors have a direct suppressive effect on bone turnover, with an imbalance between collagen synthesis and degradation.