The clinical expression of hemochromatosis in Oslo, Norway. Excessive oral iron intake may lead to secondary hemochromatosis even in HFE C282Y mutation negative subjects.

BACKGROUND: The prevalence of hereditary hemochromatosis in Norway is one of the highest reported in the world. However, the clinical presentation in patients with hemochromatosis in Norway seems to be different compared with recent studies elsewhere. The aim of this study was to investigate patients with hemochromatosis in one community hospital in Norway and to study the prevalence of the C282Y mutation. METHODS: One hundred and twenty patients were consecutively admitted to one medical department in Oslo. Serum transferrin and ferritin concentrations were measured in all patients, and a percutaneous liver biopsy was obtained in 108 of 120 (90%) patients. Stainable iron (Perls stain) in hepatocytes was graded from 0 to 4+ and fibrosis from 1 to 4. Genotyping for the C282Y and H63D mutation in the HFE gene was performed by PCR-RFLP. RESULTS: Forty-eight (40%) of the patients suffered from tiredness and astenia and 29 (24%) had typical arthropathy. Only 5 of 105 (4.5%) had biopsy confirmed cirrhosis and 5 had diabetes mellitus. Patients referred from a blood bank had significantly less symptoms and signs compared with other patients. Twenty-one of 120 (17.5%) patients were C282Y mutation negative. Seventeen (81%) of these patients (16 women and 1 man) had a history of extensive oral iron intake lasting from 5 to 50 years. When excluding those with extensive oral iron intake (n = 17), 92 of 103 (89%) were homozygous for the C282Y mutation, 7 (7%) were heterozygous including 3 compound heterozygous and 4 (4%) were mutation negative. CONCLUSIONS: Only a minority of our patients with hemochromatosis had a far advanced disease at the time of diagnosis (less than 5% had cirrhosis) and hemochromatosis in a majority of the C282Y mutation negative patients was associated with excessive oral iron intake for several years.

Prevalence of hemochromatosis among first-time and repeat blood donors in Norway.

BACKGROUND/AIMS: The observed prevalence of hemochromatosis has ranged considerably from 0.05 to 0.37% in studies requiring liver biopsy. We aimed to study the prevalence of genetic hemochromatosis among Norwegian blood donors. METHODS: We studied 10,552 healthy blood donors (5312 women and 5240 men) using serum ferritin as a screening parameter. If serum ferritin concentration was > or = 100 micrograms/l in women and > or = 200 micrograms/l in men, serum iron and transferrin (measured as total iron binding capacity = TIBC) were measured. Blood donors who repeatedly had a transferrin saturation above 40% and a ferritin concentration above these limits were referred to a hepatologist (H.B.). RESULTS: Serum ferritin was > or = 100 micrograms/l in 94/5312 (1.8%) women and > or = 200 microliters in 79/5240 (1.5%) men. Of these, 37 persons had a serum ferritin concentration above 100 micrograms/l (females) or above 200 micrograms/l (males) and a transferrin saturation above 40%. Nineteen of them (13 men and 6 women, median age 36 years, range 28-68) were identified as having hemochromatosis on the basis of increased hepatic iron index. Serum ferritin ranged from 111 to 1980 micrograms/l (median 357 micrograms/l and transferrin saturation from 50 to 100% (median 92%), hepatic iron from 48 to 471 mumol/g dry weight (median 118 mumol/g) and hepatic iron index from 1.5 to 12.1 (median 3.0). One person had cirrhosis and none had diabetes. The prevalence of hemochromatosis was significantly higher among first-time blood donors (12 out of 3500 [3.4/1000]) compared with repeat donors (7 out of 7052 [1/1000]), p < 0.005. CONCLUSIONS: The observed prevalence of hemochromatosis in Norwegian first-time blood donors of 0.34% is comparable to recently observed prevalences in other studies. However, the use of serum ferritin as a first-step screening tool may have failed to detect hemochromatosis in the early stage where iron overload has not yet occurred.

An automated C4b binding protein assay compared with an electroimmunoassay in a clinical material.

We have evaluated an automated, simplified, turbidimetric method for the measurement of the C4b binding protein (C4bBP). A comparison with a manually performed electroimmunoassay in plasma samples referred for coagulation analysis (n = 80) revealed a correlation coefficient of 0.88. Lipaemic plasma is not suitable for analysis, whereas moderately haemolytic or icteric plasma may be used with the present method. In young and middle-aged patients (n = 33) investigated 3 or more months after an episode with thrombosis of unknown reason, the mean C4bBP concentration was not significantly different from the mean found in healthy controls (n = 38). This result is in accordance with the hypothesis that C4bBP is an acute phase reactant. The results indicate that the turbidimetric assay may replace the electroimmunoassay in clinical work.

A comparison between two commercial methods for determining carbohydrate deficient transferrin (CDT).

The performance of CDTect (Kabi-Pharmacia, Uppsala, Sweden) and two versions of AXIS % CDT (AXIS Biochemicals, Oslo, Norway) for determining carbohydrate deficient transferrin (CDT) was examined in 502 consecutive patients admitted to the Department of Medicine, Aker University Hospital. The sensitivity for detecting an alcohol consumption > or = 50 g/day for the last 4 weeks was 69% for CDTect, 65% for AXIS % CDT, version 1 (AX CDT 1) and 50% for AXIS % CDT, version 2 (AX CDT 2). The specificity at the same level of alcohol consumption, markedly differed between the two methods: 92%, 76% and 90% for CDTect, AX CDT 1 and AX CDT 2, respectively. The variation coefficient (day-to-day) was 10%, 22% and 10% for CDTect, AX CDT 1 and AX CDT 2, respectively.

Carbohydrate-deficient transferrin and other markers of high alcohol consumption: a study of 502 patients admitted consecutively to a medical department.

An isoform of transferrin, carbohydrate-deficient transferrin (CDT) is increased in a high percentage of abusing alcoholics and has been found superior in its specificity compared with other biological markers. We used serum CDT as a screening parameter in 502 patients consecutively admitted to our medical department during a 4-week period. The intake of ethanol during the last 4 weeks was registrated by personal interviews and the mean daily consumption calculated. Serum CDT was measured at admission (CDTect) and compared with gamma-glutamyltranspeptidase (GGT), AST, ALT, and mean corpuscular volume (MCV). Serum CDT detected 18 of 26 (69%) patients who consumed > 50 g ethanol daily. The clinical sensitivity of CDT of detection ethanol consumption > 50 g daily was 69%, compared with 73%, 50%, 35%, and 52% for increased values of GGT, AST, ALT, and MCV, respectively. Altogether, 38 of 476 patients (8%) with a daily ethanol consumption < 50 g also had increased serum CDT levels. The specificity of CDT was 92%, compared with 75%, 82%, 86%, and 85% for GGT, AST, ALT, and MCV, respectively. In the 60 patients who consumed > 10 g ethanol daily, we found a significantly positive correlation between CDT and ethanol consumption (r = 0.52, p < 0.001). A positive correlation was also found between serum transferrin and CDT (r = 0.51, p < 0.001). In conclusion, the specificity of CDT is much higher compared with GGT in detecting alcohol abuse. Some acute and chronic illnesses may increase the serum level of CDT. False-positive CDT levels may be caused by changes in serum transferrin concentration.

Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver diseases.

OBJECTIVES: To compare serum ferritin concentration and transferrin saturation in patients with alcoholic and non-alcoholic chronic liver diseases. DESIGN: Consecutive patients with liver diseases. SETTING: The department of internal medicine in a teaching hospital. SUBJECTS: Three hundred and twelve patients with different liver diseases consecutively admitted between 1987 and 1992. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Fasting serum iron, transferrin and ferritin. RESULTS: Serum ferritin was increased above 200 micrograms L-1 in all 18 patients with haemochromatosis (range 310-6500 micrograms L-1), in 64 of 111 alcoholics (58%) and in 30 of 137 (22%) with chronic non-alcoholic liver diseases (P < 0.01). Twelve of 111 alcoholics (11%) had serum ferritin above 1000 micrograms L-1 compared with one of 137 (0.7%) with chronic non-alcoholic liver diseases. In 13 alcoholics who abstained after admission, serum ferritin decreased from 1483 micrograms L1 +/- 1134 to 388 micrograms L-1 +/- 237 (P < 0.001) after 1 1/2 to 6 weeks. The transferrin saturation was increased above 62% in 13 of 18 patients (72%) with haemochromatosis, in 16 of 105 alcoholics (15.2%) and in three of 132 (2.3%) with chronic non-alcoholic liver disease (P < 0.01). CONCLUSION: Serum ferritin is more frequently elevated in abusing patients with alcoholic liver disease than in patients with other chronic liver diseases such as autoimmune liver diseases and hepatitis C. Because serum ferritin decreases rapidly during abstinence, the measurement of ferritin for the detection of haemochromatosis in patients abusing alcohol should be postponed until the patients are abstaining. Most of the patients with increased serum ferritin have normal transferrin saturation values which can be used to separate them from haemochromatosis.

[Computer tomography in the detection of hemochromatosis]. / Computertomografi til påvisning av hemokromatose.

Computed tomography (CT) was performed to estimate the density of the hepatic and splenic parenchyma in 18 patients with hemochromatosis. The mean CT density was 79 +/- 21 Hounsfield units compared with 61 +/- 9 (p < 0.01) in 31 controls without hepatic disease. Increased density above 79 Hounsfield units was found in eight patients out of 18 (44%). The highest density (125 Hounsfield units) was found in a patient with a serum ferritin of 6500 micrograms/l. There was an association between CT density and serum ferritin (r = 0.72, p < 0.01). The difference in density between liver and spleen gave better discrimination between patients and controls: 12 of 18 (67%) showed an increased difference in density between liver and spleen. We conclude that CT represents a non-invasive alternative to liver biopsy in cases where the latter is contraindicated. However, CT is not sensitive when serum ferritin is below 1,000 micrograms/l.

[Clinical experience with early hemochromatosis]. / Klinisk erfaring med tidlig hemokromatose.

During the period 1986-93 22 patients were diagnosed as having primary hemochromatosis. Only 11 of them had elevated aminotransferases. Transferrin saturation was higher > 63% in 17 (77%) and serum-ferritin was higher in all the patients. (257 mumol/l to 6,500 mumol/l). A percutaneous liver biopsy was performed in 20 patients, all of whom showed a characteristic grading from 2 + to 4+ using Perls' stain. Two males had cirrhosis with simultaneous hepatocellular carcinoma, and another two had cirrhosis. One patient had diabetes mellitus type I. We conclude that fasting serum-iron and transferrin should be determined in all subjects over 40 years of age and in patients with chronic elevation of liver enzymes. If transferrin saturation is higher than 50% in females and 60% in males, serum ferritin should be determined. A percutaneous liver biopsy should be performed if both values are higher than normal. Screening of siblings is important because of the autosomal recessive pattern of inheritance.

[Children and health. A questionnaire survey of 12-year-old children]. / Barn og helse. En spørreundersøkelse blant 12-åringer.

Medicalization, implying that solutions to everyday or existential problems are being sought within the framework of the health care system, seems to be increasing. Morbidity has been related to socioeconomic status. This study aims at finding out how children perceive their own health condition and whether this is related to socioeconomic conditions. 192 pupils aged 12 years from a rural district and from two districts of Oslo with different socioeconomical conditions reported their health condition during the last school term by means of a questionnaire. There was a high prevalence of complaints from the children. 33% reported insomnia, and 14% had frequent episodes of headache. Nearly 50% reported the presence of one or more chronic diseases. The health problems were not related to gender or nationality. Except for dental health, we found no relation between reported sickness and the children's socioeconomic background.

Free protein S deficiency in patients with Crohn's disease.

Multifocal intestinal infarctions, due to thrombosis in small vessels, might be a pathogenetic mechanism for Crohn's disease (CD). Deficiency of free protein S may contribute to the development of such thrombotic occlusions. In the present study free protein S was measured in 54 patients with CD. In 31 patients (57.4%) the plasma concentrations of free protein S were below the lower normal range. The mean value of free protein S in CD patients was 72.2%, as compared with 97.5% in healthy subjects (p < 0.01). The concentrations of C4b-binding protein and protein C were similar in the two groups. Free protein S levels were not correlated to disease activity, previous surgery or complications, extraintestinal manifestations, or current medical therapy. The impairment of the protein S/protein C/thrombomodulin system found in patients with CD favours coagulation and might be of importance for both the development of CD and its thromboembolic complications.

[Protein S deficiency, acute phase reaction and thrombosis]. / Protein S-mangel, akuttfasereaksjon og trombose.

Protein S deficiency increases risk of thrombosis. At present, we have information on 63 Norwegian individuals with hereditary protein S deficiency belonging to 25 different families. 42 of the individuals have experienced at least one thromboembolic episode, and seven a cerebral infarction before the age of 70 years. The amount of free protein S in plasma is dependent on variation of the acute phase protein C4b-binding protein (C4bBP). Acute phase response with increased C4bBP induces free protein S deficiency, and increases risk of thrombosis. In patients with protein S deficiency, warfarin may reduce free protein S to critically low levels, and thus explain why, in some patients, recurrent thrombosis occurs during warfarin treatment. In this situation, warfarin should be replaced by heparin.

Serum carbohydrate-deficient transferrin as a marker of alcohol consumption in patients with chronic liver diseases.

We measured serum levels of carbohydrate deficient transferrin (CDT) in 420 subjects: 100 healthy blood donors, 82 healthy employees, 70 abstaining patients with different chronic nonalcoholic liver disease, 16 abstaining patients with alcoholic fatty liver, 50 abstaining patients with alcoholic liver cirrhosis, 25 abusing patients with alcoholic fatty liver, 41 abusing patients with alcoholic liver cirrhosis, and 36 patients with alcohol dependence syndrome with a daily ethanol consumption of 173 +/- 120 g the last 4 weeks before blood was drawn. In controls the serum level of CDT was significantly higher in females compared with males (17.7 +/- 5.1 and 13.7 +/- 3.8 units/liter, respectively), and the upper normal limit was defined as 27 and 20 units/liter. Sixty-two of 102 (60.8%) abusing patients with alcoholic liver disease had increased levels of CDT compared with 1 of 66 abstaining (1.5%) patients with alcoholic liver disease, and 10 of 70 (14.3%) abstaining patients with nonalcoholic liver disease among them 3 with primary biliary cirrhosis and 2 with chronic autoimmune hepatitis. No correlation was found between serum CDT and gamma-glutamyltranspeptidase (GGT), AST, ALT, and mean red cell volume (MCV). The sensitivity and specificity for serum CDT was 61 and 92%, respectively, compared with 85 and 18% for GGT and 70 and 66% for MCV. No advantage was gained by using the CDT/transferrin ratio. Our study confirms that CDT is a specific marker for chronic alcohol abuse, except in few patients with other chronic liver diseases. Serum CDT seems to be a better indicator of abstention than GGT; AST and MCV in patients with alcoholic liver disease. However, in our hands CDT is not so sensitive for alcohol abuse in patients with liver disease as reported earlier in unselected alcoholics.

Free protein S deficiency in patients with chronic inflammatory bowel disease.

Free protein S, protein C, and C4b-binding protein (C4b-BP) were measured in randomly selected outpatients: 22 with Crohn's disease (CD) and 16 with ulcerative colitis (UC). Active disease was recorded in 10 patients with CD and 4 with UC. Fourteen patients (63.6%) with CD and 4 (25%) with UC had free protein S values below the normal range, with mean values of 62% and 78% of that found in healthy control subjects (p < 0.01). The C4b-BP level was 127% in patients with CD as compared with 89% in both healthy subjects and UC patients (p < 0.01). The protein C levels were similar in the three groups. The present results add to the factors already known favouring thromboembolic complications in inflammatory bowel disease and which might play a major role both for the pathogenesis and for the increased tendency to venous thromboembolism in these diseases.

[Chronic hepatitis C. Experience with 50 patients]. / Kronisk hepatitt C. Erfaring med 50 pasienter.

We studied 50 patients (36 males and 14 females) with chronic hepatitis C who were admitted consecutively to our medical department during the period 1987-91. Eight patients (16%) had had a blood transfusion, 17 (34%) had used intravenous drugs and 25 (50%) were "sporadic cases" with no identifiable risk factor except that at least five had been tattooed. Most of the patients had moderate symptoms, including tiredness and asthenia. Few were jaundiced. A percutaneous liver biopsy was performed in 27 patients and showed chronic persistent hepatitis in 12 of them, chronic active hepatitis in six and cirrhosis in nine. Three patients with cirrhosis died; one from hepatoma, one from an endstage cirrhosis with bleeding and coma hepaticum, and one from septicaemia.

Recurrent venous thrombosis during warfarin treatment related to acquired protein S deficiency.

Failure of warfarin to prevent new thrombotic processes was observed in three patients with very low free protein S concentrations and high C4b-binding protein (C4bBP) concentrations, and in one patient with hereditary protein S deficiency. We suggest that an increase in C4bBP reduces the free Protein S level, and warfarin treatment causes an additional decrease of free protein S. The four patients presented indicate that such reductions are of clinical importance. Heparin seems preferable as an anticoagulant in this situation, as warfarin given alone is ineffective, or may even be harmful. In a group of pancreatic cancer patients with advanced disease, subnormal mean free protein S was found, whereas mean total protein S concentration, and mean C4bBP concentrations were significantly higher (p less than 0.01) than in healthy controls. These findings indicate that an increase in C4bBP may induce free protein S deficiency contributing to the increased thrombotic tendency in this group of patients. The correlation between free protein S and C4bBP was 0.11, (n.s.), between total protein S and C4bBP 0.73 (p less than 0.0001).

Reduced concentration of hepatic alpha-tocopherol in patients with alcoholic liver cirrhosis.

The concentration of alpha-tocopherol was measured in liver biopsy specimens obtained from 83 patients with alcoholic and non-alcoholic liver diseases. The mean hepatic vitamin E content (as alpha-tocopherol) was significantly lower in 23 patients with alcoholic cirrhosis (17.6 +/- 12.1 nmol/mg wet weight liver), compared with 12 patients with normal liver histology (39.2 +/- 29.7 nmol/mg, P less than 0.01). The mean serum concentration of alpha-tocopherol was lower in patients with alcoholic cirrhosis (13.9 +/- 7.0 mumol/l) than in individuals with alcoholic fatty liver (21.3 +/- 9.3 mumol/l, P less than 0.01) and patients with normal liver histology (23.4 +/- 11.6 mumol/l, P less than 0.01). A decreased ratio of serum alpha-tocopherol/total serum lipids was also observed in patients with alcoholic cirrhosis, compared with patients with normal liver histology (P less than 0.05). There was a significant correlation between concentrations of alpha-tocopherol in liver and serum (r = 0.43, P less than 0.001). Furthermore, serum alpha-tocopherol correlated with retinol (r = 0.53, P less than 0.001), selenium (r = 0.45, P less than 0.001), and albumin (r = 0.37, P less than 0.001) in serum. We suggest that the reduced content of hepatic alpha-tocopherol observed in some patients may play a role in ethanol-induced lipid peroxidation.

New semiquantitative dipstick test for microalbuminuria.

OBJECTIVE: We compared a new semiquantitative dipstick test for microalbuminuria (Micral-Test) with a quantitative immunoturbidimetric method. RESEARCH DESIGN AND METHODS: This correlation study was performed at a pediatric and medical outpatient clinic at a university hospital. Overnight urine samples containing less than 200 mg/L albumin from 186 diabetic patients were analyzed. RESULTS: The correlation coefficient between the new semiquantitative method and the immunoturbidimetric reference method was 0.82. Elevated albumin concentration was defined as greater than 20 mg/L albumin in overnight urine, and the prevalence of samples with values above this level was 28%. By this definition, the Micral-Test assay level greater than or equal to 20 mg/L had a sensitivity of 92.3% and a specificity of 82.1%. Of the diabetic subjects, 84.9% were correctly classified as having elevated urinary albumin concentration or not. CONCLUSIONS: The Micral-Test is useful for in-clinic screening for elevated urinary albumin concentration and monitoring the development of urinary albumin excretion in the low microalbuminuric range.

Early morning glycaemia and the metabolic consequences of delaying breakfast/morning insulin. A comparison of continuous subcutaneous insulin infusion and multiple injection therapy with human isophane or human ultralente insulin at bedtime in insulin-dependent diabetics.

We studied morning glycaemia and metabolic consequences of delaying morning insulin/breakfast in insulin-dependent diabetics on (i) continuous subcutaneous insulin infusion (CSII) (n = 27), (ii) multiple-injection therapy (MI) with human isophane insulin at bedtime (MI/human isophane) (n = 23) and (iii) MI with human ultralente insulin at bedtime (MI/human ultralente) (n = 14). After an overnight fast, food and insulin (except for the basal infusion on CSII) were withheld, and blood glucose, serum free insulin and serum betahydroxybutyrate were followed from 0800 hours to 1300 hours. At all times blood glucose was lowest on CSII, intermediate on MI/human isophane and highest on MI/human ultralente; serum free insulin was highest on CSII, intermediate on MI/human ultralente and lowest on MI/human isophane; serum betahydroxybutyrate was lowest on CSII, intermediate on MI/human ultralente and highest on MI/human isophane. Blood glucose rose significantly on MI/human isophane (p less than 0.001) and CSII (p less than 0.02); serum free insulin declined significantly on MI/human isophane (p less than 0.001), and betahydroxybutyrate rose significantly on all regimens. Morning metabolic control is better with CSII than MI. Human isophane insulin is preferable to human ultralente insulin overnight in MI. Delaying morning insulin is not advisable on intensified insulin regimens, being most unfavourable with MI/human isophane.

Protein C: an automated activity assay.

Protein C in citrated plasma is found to be specifically activated by the snake venom derivative Protac, and the activator is used in a simple, automated assay method. The activation is completed in less than 120 s and an isolation of protein C from its inhibitor before activation is not necessary. The activated protein C is determined with the chromogenic substrate S-2366. Therapeutic concentrations of heparin in the test sample do not influence the result. A strong positive correlation to immunoassay of protein C was found (r = 0.92). Three cases of probable hereditary protein C deficiency belonging to the same family were discovered during the study.