Oliver C.K. Ma

A controlled trial of interferon with or without prednisone priming for chronic hepatitis B

In a randomized, controlled trial of recombinant interferon alfa-2b with or without prednisone priming in Chinese adults with chronic hepatitis B virus infection, stratified randomization for pretreatment serum alanine aminotransferase levels was done. Partial or complete antiviral responses were achieved in 17 (21.5%) of 79 treated patients and 3 (8.3%) of 36 controls (P = 0.14). The response to interferon treatment was significantly better in those who had elevated pretreatment transaminase levels and comparable to that reported in white patients [15 (38.5%) of 39 patients compared with 2 (5%) of 40 who had normal pretreatment transaminase levels (P = 0.0005)]. The spontaneous seroconversion rate was also higher among the controls with elevated transaminase levels [3 (18.8%) of 16 compared with 0 of 20 with normal transaminase levels], but this difference was not statistically significant (P = 0.16). Among the interferon-treated patients, prednisone priming appeared to have a marginal benefit over treatment with interferon alone in patients with elevated transaminase levels (43% vs. 33%), but not in those with normal transaminase levels (0% vs. 9.5%). It was confirmed that Chinese patients with normal transaminase levels respond very poorly to interferon alfa therapy. However, the response was significantly better in patients with elevated transaminase levels.

Long-term follow-up of chronic hepatitis B patients treated with interferon alfa

BACKGROUND There is very little data on the long-term outcome of patients with chronic hepatitis B after interferon therapy. A 6-year follow-up of two interferon trials in chronic hepatitis B patients is reported. METHODS One hundred twenty-eight Chinese adults with chronic hepatitis B who received interferon therapy were followed for 19-79 months (median 41 months). Twenty-nine patients lost hepatitis B e antigen and two also lost hepatitis B surface antigen within 1 year of treatment. RESULTS Seven (24%) responders reactivated. Twenty-eight (28%) nonresponders had sustained clearance of hepatitis B e antigen during follow-up. Delayed clearance of hepatitis B e antigen occurred more frequently in nonresponders who had elevated pretreatment serum transaminase levels. (P = 0.002). Serum hepatitis B virus DNA became undetectable by polymerase chain reaction assay in both responders who lost hepatitis B surface antigen but in only 8 (17%) patients who lost hepatitis B e antigen only. Delayed clearance of hepatitis B surface antigen was not seen in any of the 48 patients who had sustained clearance of hepatitis B e antigen. CONCLUSIONS Contrary to reports from Western countries, complete elimination of markers of hepatitis B virus infection was uncommon in Chinese patients with chronic hepatitis B who underwent interferon therapy despite similar duration of follow-up.

Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity

AbstractWilson disease (WD), an autosomal recessive disorder of copper transport, is the most common inherited liver disorder in Hong Kong Chinese. This was the first local study to elucidate the molecular basis and establish an effective DNA-based diagnostic protocol. The ATP7B genes of 65 patients were amplified by polymerase chain reaction (PCR) and sequenced. Haplotype analysis was performed using D13S301, D13S314, and D13S316. The p.L770L/p.R778L status in 660 subjects was determined to estimate WD prevalence. Allele age of p.R778L was determined by the smallest homozygosity region between D13S301 and D13S270. We identified 42 different mutations with 17 being novel. p.R778L (17.3%) was the most prevalent. Exons 2, 8, 12, 13, and 16 harbored 70% mutations. Thirty-two haplotypes were associated with WD chromosomes. The estimated prevalence rate was 1 in 5,400. Three out of 660 normal subjects had p.L770L/p.R778L. In the remaining 657 individuals, neither p.L770L nor p.R778L was found. We characterized a Hong Kong Chinese-specific ATP7B mutation spectrum with great genetic diversity. Exons 2, 8, 12, 13, and 16 should be screened first. The perfect linkage disequilibrium suggested that p.R778L and its private polymorphism p.L770L originated from a single ancestor. This East-Asian-specific mutation p.R778L/p.L770L is aged at least 5,500 years.

Interferon alfa therapy in patients with chronic hepatitis B virus infection

Pretrial and posttrial liver biopsy samples from 124 adult patients who participated in two randomized, controlled trials of interferon alfa therapy for chronic hepatitis B virus (HBV) infection were analyzed to determine the effects of interferon on the replication of HBV in the liver. Replicative forms of HBV DNA were detected in the pretrial biopsy samples from all and posttrial biopsy samples from 74% treated patients and 86% controls. Replicative forms of HBV DNA were detected in the posttrial biopsy samples from all patients who remained positive for hepatitis B e antigen and HBV DNA in the serum, in 77% treated patients and 80% controls who cleared HBV DNA in the serum but who remained positive for hepatitis B e antigen, but in only 19% treated patients and 40% controls who cleared HBV DNA as well as hepatitis B e antigen in the serum. Serum alanine aminotransferase levels were significantly lower in patients whose posttrial biopsies did not contain replicative forms of HBV DNA. In summary, we demonstrated that in most patients with chronic HBV infection treated with interferon alfa, serological response was associated with the disappearance of replicative forms of HBV DNA in the liver.

Genetic influence of the R/Q353 genotype on factor VII activity is overwhelmed by environmental factors in Chinese patients with Type II (non-insulin-dependent) diabetes mellitus

Summary We studied the effects of genetic and environmental influences on factor VII coagulant activity (VIIc) in Chinese diabetic patients (263 with Type II [non-insulin-dependent] diabetes mellitus, 78 with Type I [insulin-dependent] diabetes mellitus) and 143 normal control subjects. VIIc was measured by a one-stage biological assay. The R/Q353 or Msp1 polymorphism at codon 353 of the factor VII gene was detected after Msp1 digestion of polymerase chain reaction-amplified genomic DNA. In both diabetic and control subjects the allele frequencies of the R (M1) and Q (M2) alleles were 0.96 and 0.04; the corresponding reported frequencies in Caucasians being 0.90 and 0.10: VIIc were 21 % lower in Chinese control subjects and Type I diabetic patients with R/Q, compared with R/R subjects (p < 0.001 and p < 0.05). The corresponding difference was 4 % for Type II diabetc patients (p = NS). Type II diabetic patients had higher mean VIIc levels than control subjects and Type I diabetic patients (p < 0.01); they were also older, and had higher serum creatinine and triglyceride (all p < 0.01). They also had higher VIIc levels than an age-matched older control group (p < 0.01; n = 182) in whom the genotype effect was clearly seen. On stepwise linear regression analysis, the significant independent determinants of VIIc were serum triglyceride (contributing 20 % and 25 % to variance in control subjects and diabetic patients), the R/Q353 genotype (contributing to 12 % of the variance in control subjects but only 1 % in diabetic patients), age and total cholesterol in all subjects, and in the diabetic patients female sex, urinary albumin excretion rate and serum creatinine. VIIc was higher in diabetic patients with macroangiopathy and retinopathy (both p < 0.0001). We conclude that compared with Caucasians, the Q allele frequency is significantly lower in these Chinese subjects. Plasma VIIc is determined by both genetic and environmental influences such that in Chinese Type II diabetic patients, the effect of environmental factors predominates, almost negating the influence of the R/Q353 genotype. High VIIc may contribute to the increased cardiovascular risk in Type II diabetic patients. [Diabetologia (1998) 41: 760–766]

Lathosterolosis: A Disorder of Cholesterol Biosynthesis Resembling Smith-Lemli-Opitz Syndrome

Lathosterolosis is an inborn error of cholesterol biosynthesis due to deficiency of the enzyme 3-beta-hydroxysteroid-delta-5-desaturase (or sterol-C5-desaturase or SC5D). This leads to a block in conversion of lathosterol into 7-dehydrocholesterol. Only three patients with lathosterolosis have been reported in literature, of which one survived. We report a patient with dysmorphism, multiple congenital anomalies, and developmental delay, initially suspected to have Smith-Lemli-Opitz syndrome, who was later found to have elevated levels of lathosterol in both plasma and fibroblasts. Genetic study confirmed a compound heterozygous mutation in the sterol-C5-desaturase-like (SC5DL) gene on chromosome 11q23. Simvastatin was started as a treatment therapy and it resulted in normalization of blood lathosterol level and improvement in the neurodevelopmental profile. However, additional patients are needed for better delineation of the clinical spectrum, genotype-phenotype correlation, and potential efficacy of simvastatin treatment in this rare disorder. If the presence of distinctive facial features and limb anomalies raise the suspicion of a cholesterol biosynthesis defect, testing of full sterol profile is warranted as normal cholesterol or 7-dehydrocholesterol levels cannot rule out the diagnosis of cholesterol synthesis defect like lathosterolosis.

Novel Insertion 496_497insG Creating a Stop Codon D194X in a Chinese Family with X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (XALD, MIM 300100), the commonest inherited peroxisomal disorder, is characterized by central nervous system demyelination, primary adrenal failure and the systemic accumulation of saturated very long chain fatty acids (VLCFAs). The defective gene ABCD1 encodes an ATP-binding cassette (ABC) transport protein named ALDP, which functions as a crucial transporter of VLCFAs into the peroxisomes for β-oxidation. Here, we report a Chinese man with adrenomyeloneuropathy characterized by Addison’s disease and spastic paraparesis. His plasma VLCFA levels, ratios of C24:0/C22:0 and C26:0/C22:0 were all significantly elevated. We performed mutation analysis of the ABCD1 gene in the proband and the family members using direct DNA sequencing and restriction analysis. A novel insertion 496_497insG in exon 1 causing a frame shift and a premature stop codon at amino acid position 194 (D194X) was identified (GenBank accession No. NM_000033). The insertional mutation abolishes an HhaI restriction site. The same mutation was found in his mother and the eldest sister even though their clinical and biochemical abnormalities were milder. Diagnosis of XALD often relies upon the detection of elevated VLCFA levels and ratios of C26:0/C22:0 and C24:0/C22:0 in fasting blood, however, 5–15% of the obligate heterozygotes would give normal values. DNA-based testing thus remains the most reliable tool for heterozygote detection when the disease-causing mutations are known. Using restriction fragment length polymorphism with HhaI, we have devised a rapid method for the identification of the carriers among the proband’s family members and possibly for the screening of the mutations in other XALD patients.

Determinants of postprandial triglyceride and remnant-like lipoproteins in type 2 diabetes

Postprandial changes in remnant‐like lipoprotein particles (RLP) contribute to the severity of coronary heart disease in type 2 diabetes. Since the determinants of postprandial response in RLP are not well understood, this study investigated the roles of fasting triglyceride, apolipoprotein (apo) E polymorphism and insulin resistance in a group of overweight/obese Chinese type 2 diabetic subjects.

Novel mutations in myopathic form of carnitine palmitoyltransferase II deficiency in a Chinese patient

BACKGROUND Carnitine palmitoyltransferase II (CPT II) deficiency is one of the most common disorders of oxidative fatty acid metabolism. In this disorder, long-chain acylcarnitines cannot be converted to acyl CoA and there is impairment of β-oxidation of fatty acids. RESULTS In the 3 distinct clinical subtypes of CPT II deficiency, adult onset myopathic form shows mild clinical manifestations, characterized by recurrent rhabdomyolysis after intense physical stress. In this study, we report a case with adult myopathic form of CPT II deficiency presenting recurrent exercise-induced myoglobinuria. CONCLUSION The acylcarnitine profile showed characteristic CPTII deficiency profile and sequencing of the CPT2 gene showed 2 novel missense mutations p. H369Q and p G497S.

Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity (Journal of Human Genetics (2008) 53 (55-63) DOI: 10.1007/s10038-007-0218-2)

The correct name of the eighth author should be given as Sik-To Lai, not Jak-Yiu Lai.