Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population.

OBJECTIVE: The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. PATIENTS AND METHODS: 373 patients with hemochromatosis detected through routine health check-ups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 ± 5.8 years. The degree of liver fibrosis and survival were analyzed. RESULTS: Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. CONCLUSION: Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.

Characteristics and long-term outcome of patients with autoimmune hepatitis related to the initial treatment response.

OBJECTIVES: Autoimmune hepatitis (AIH) is a liver disease which, if untreated, may lead to liver cirrhosis and hepatic failure. Limited data exist regarding factors predicting the long-term outcome. The aims of this study were to investigate symptoms at presentation, prognostic features, management and treatment in relation to long-term outcome of AIH. MATERIAL AND METHODS: A cohort of 473 Swedish patients with AIH was characterized regarding initial symptoms and signs, factors predicting death and future need for liver transplantation. Survival and causes of death were retrieved from Swedish national registers. RESULTS: At diagnosis, fatigue was a predominant symptom (69%), 47% of the patients were jaundiced and 30% had liver cirrhosis. Another 10% developed cirrhosis during follow-up. Markedly elevated alanine aminotransferase levels at presentation were correlated with a better outcome. A high international normalized ratio (INR) at diagnosis was the only risk factor predicting a need for later liver transplantation. Histological cirrhosis, decompensation and non-response to initial treatment were all factors that correlated with a worse outcome. Overall life expectancy was generally favourable. However, most deaths were liver-related, e.g. liver failure, shock and gastrointestinal bleeding. CONCLUSIONS: Cirrhosis at diagnosis, a non-response to initial immune-suppressive treatment or elevated INR values were associated with worse outcome and a need for later liver transplantation. In contrast, an acute hepatitis-like onset with intact synthetic capacity indicated a good response to treatment and favourable long-term prognosis. Lifetime maintenance therapy is most often required.

Increased mortality risk in patients with phenotypic hereditary hemochromatosis but not in their first-degree relatives.

BACKGROUND & AIMS: Hereditary hemochromatosis (HH) is an autosomal-recessive disorder characterized by iron overload. Relatives of HH patients were screened and those with HH-associated mutations and an increased iron load were identified. However, little is known about their mortality or strategies for their management. We assessed mortality among Swedish patients with HH and their first-degree relatives using health and census registers. METHODS: We performed a matched population-based cohort study of 3832 patients with HH and their 14,496 first-degree relatives using data collected from 1990 through 2007. Mortality data from these groups were compared with that of 38,969 population controls and their 143,349 first-degree relatives using Cox regression analyses. RESULTS: Patients identified on the basis of hospitalization with HH had an increased risk (relative risk [RR]) for death (RR, 2.45; 95% confidence interval [CI], 2.27-2.64; 857 deaths). Patients identified through other means had a mortality risk that was lower than those identified in the hospital but higher than controls (RR, 1.15; 95% CI, 1.00-1.33; 216 deaths). Their first-degree relatives had only a marginally increased mortality risk (RR, 1.05; 95% CI, 1.01-1.10); this RR was similar to that of patients' spouses (RR, 1.09; 95% CI, 0.86-1.38; 82 deaths). Patients with HH who also had a family history of HH did not have an increased mortality risk compared with other groups (RR, 1.05; 95% CI, 0.67-1.62; 21 deaths). CONCLUSIONS: Patients with HH have a modestly increased mortality risk compared with controls. The mortality of relatives is increased marginally compared with controls, and is similar among biological and nonbiological relatives.

Hepatic and extrahepatic malignancies in autoimmune hepatitis. A long-term follow-up in 473 Swedish patients.

BACKGROUND/AIMS: Autoimmune Hepatitis (AIH) is a liver disease which may lead to liver cirrhosis. Cirrhosis is a well-known risk factor for hepatocellular cancer. Lymphoma is a disease, where immune modulating drugs as well as the autoimmune disease itself may contribute to the elevated risk. The aim was to investigate the risks of malignancies in a large cohort of AIH patients. METHODS: Four hundred and seventy-three patients with AIH were matched to the Swedish national cancer register as well as to the death cause register. RESULTS: We found an overall higher risk of malignancies in the cohort of AIH patients from the date of diagnosis with a SIR of 1.51 (95% CI 1.10-2.03). SIR in the subpopulation of well defined catchment areas and complete case finding was 23.28 (95% CI 7.5-54.34) for HCC. Lymphomas were found a SIR of 13.09 (95% CI 4.22-30.56). CONCLUSIONS: There was an overall increased risk of malignancies in a cohort of AIH patients, which manly was caused by hepatobiliary cancers. However, the true risk of HCC in an AIH cirrhotic cohort has yet to be investigated. A significantly higher risk of lymphomas was also found, but no clear cut association to the use of immune modulators.

Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: The importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC. METHODS: Subjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register. RESULTS: The risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6-84.4), 11.1 (3.3-37.8), and 2.3 (0.9-6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3-4.9) and for Crohn's disease 1.4 (0.8-2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9-18.9). CONCLUSIONS: First-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC.

Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study.

OBJECTIVE: Autoimmune hepatitis (AIH) is a chronic liver disease, which if untreated can lead to cirrhosis and hepatic failure. The aim of the study was to investigate the incidence, prevalence, diagnostic tradition and clinical initial presentation of AIH. MATERIAL AND METHODS: Analyses were performed in 473 patients identified as having probable or definite AIH. RESULTS: The incidence of AIH was 0.85/100,000 (95% CI 0.69-1.01) inhabitants, which is somewhat lower than reported previously. The point prevalence amounted to 10.7/100,000 (95% CI 8.8-13.1), and 76% of the cases were females. The age-related incidence curve was bimodal but men were found to have only one incidence peak in the late teens, whereas women had a peak after menopause. AIH was presented as a spectrum of clinical settings from detected "en passant" to acute liver failure. Almost 30% of patients already had liver cirrhosis at diagnosis. Autoantibodies indicative of AIH type 1 were found in 79% of cases. Other concomitant autoimmune diseases were frequently found (49%). CONCLUSIONS: The incidence and prevalence figures confirm that AIH is a fairly uncommon disease in the Swedish population. Symptoms at presentation were unspecific, but almost half of the patients were jaundiced, with around 30% having liver cirrhosis. The majority of Swedish AIH patients had AIH type 1.

Long-term colectomy rate after intensive intravenous corticosteroid therapy for ulcerative colitis prior to the immunosuppressive treatment era.

OBJECTIVES: Corticosteroids are a cornerstone in the treatment of a severe attack of ulcerative colitis (UC). The long-term prognosis in this patient group is not well described. We studied the long-term colectomy and relapse rates in patients given intensive intravenous corticosteroid treatment (IIVT) for acute UC. METHODS: A retrospective clinical study of 158 patients with UC treated in 1975-1982 with IIVT. Patients were followed-up to death, colectomy or last visit. RESULTS: A total of 11 patients were excluded due to change of diagnosis (N = 10) or lost to follow-up (N = 1). The indication for index IIVT in the remaining 147 patients was a severe attack (N = 61), a moderately severe attack (N = 45), a mild attack (N = 29) or chronic continuous disease (N = 12). The median (range) duration of follow-up was 173 (4-271) months in patients escaping colectomy during the first 3 months. Three months after IIVT, the colectomy rates were 28/61 (46%) in a severe attack, 4/45 (9%) in a moderately severe, and 1/29 (3%) in a mild attack. After 10 yr, the colectomy rates were 39/61 (64%), 22/45 (49%), and 8/29 (28%), respectively. During follow-up, neither colectomy incidence beyond 3 months, time to first relapse nor relapse incidence was influenced by severity of initial attack, except for a lower relapse incidence after a severe attack. CONCLUSIONS: In patients escaping colectomy during the first 3 months after IIVT, the future prognosis was similar irrespective of initial disease severity.

Autoimmune hepatitis among fertile women: strategies during pregnancy and breastfeeding?

OBJECTIVE: In published studies there is a lack of data about the risks, management and how women with autoimmune hepatitis (AIH) decide on and are advised about pregnancy. The aim of this study was to investigate how women with AIH consider pregnancies, are advised and pharmacologically treated, as well as the outcome. MATERIAL AND METHODS: A questionnaire was mailed to 128 women with AIH diagnosed during their fertile period and data from the Swedish National Birth Register was also used for matched controls. RESULTS: There was an 83% response rate to the questionnaires. Sixty-three pregnancies were reported by 35 women. 48% did not consult their doctors before getting pregnant. More than half of the women reduced or stopped the immune suppression during pregnancy or breastfeeding. Some women were advised to abstain from pregnancy or even to have an abortion. Caesarean sections were performed more frequently in the AIH group (16% compared with 6.5% in the control group p<0.01). There were no significant differences in the number of stillborn infants or infants with malformations. However, 30% of the patients experienced flare-up after delivery. CONCLUSIONS: In general, the outcome of pregnancy in women with AIH seems to be good. Current pharmacological treatment appears to be safe, including azathioprine during pregnancy and lactation. After delivery an active preparedness to increase pharmacotherapy should be considered.

The Short Health Scale: a valid measure of subjective health in ulcerative colitis.

OBJECTIVE: Assessment of health-related quality of life (HRQOL) is important in both clinical practice and clinical trials, and several multi-item questionnaires are currently in use. We have devised and evaluated a simplified four-item questionnaire, the Short Health Scale (SHS), representing each of four health dimensions: (a) symptom burden, (b) social function, (c) disease-related worry and (d) general well-being. MATERIAL AND METHODS: Three hundred patients with ulcerative colitis completed the SHS and three other HRQOL questionnaires (IBDQ, RFIPC and PGWB). Half of the patients repeated the questionnaires after 6 months - or earlier if disease activity changed. Test-retest reliability was derived from measurements of the SHS questions, 2 weeks apart, on 18 patients in remission. RESULTS: Patients in relapse scored higher on each of the four SHS questions than patients in remission (p < 0.001). Each of the four SHS scores were associated with results of their corresponding health dimension obtained with the other three questionnaires (rs=0.57-0.78, p < 0.001) (validity). The results of the SHS proved stable on repeated measurement with a 2-week interval in patients in remission (rs=0.71-0.91, p < 0.01) (test-retest reliability). Patients with a change in disease activity had a significant change in their SHS scores (p < 0.05) (responsiveness). CONCLUSIONS: The SHS is a valid, reliable and responsive measure of subjective health in patients with ulcerative colitis. It is simple to administer, quickly completed and the results do not need further calculations. The SHS can be used in clinical trials and in clinical practice to identify the patient's main problems affecting health.

High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study.

BACKGROUND & AIMS: There is no medical treatment of proven benefit for primary sclerosing cholangitis. This study aimed at studying the effect of a higher dose of ursodeoxycholic acid than previously used on survival, symptoms, biochemistry, and quality of life in this disease. METHODS: A randomized placebo-controlled study was performed in tertiary and secondary gastroenterology units. A total of 219 patients were randomized to 17 to 23 mg/kg body weight per day of ursodeoxycholic acid (n = 110) or placebo (n = 109) for 5 years. Follow-up data are available from 97 patients randomized to ursodeoxycholic acid and for 101 randomized to placebo. Quality of life was assessed by using the Medical Outcomes Study 36-item Short-Form Health Survey. RESULTS: The combined end point "death or liver transplantation" occurred in 7 of 97 (7.2%) patients in the ursodeoxycholic acid group vs 11 of 101 (10.9%) patients in the placebo group (P = .368; 95% confidence interval, -12.2% to 4.7%). The occurrence of liver transplantation as a single end point showed a similar positive trend for ursodeoxycholic acid treatment (5/97 [5.2%] vs 8/101 [7.9%]; 95% confidence interval, -10.4% to 4.6%). Three ursodeoxycholic acid and 4 placebo patients died from cholangiocarcinoma, and 1 placebo patient died from liver failure. Alkaline phosphatase and alanine aminotransferase tended to decrease during the first 6 months. There were no differences between the 2 groups in symptoms or quality of life. Analyses of serum ursodeoxycholic acid concentration gave no evidence that noncompliance may have influenced the results. CONCLUSIONS: This study found no statistically significant beneficial effect of a higher dose of ursodeoxycholic acid than previously used on survival or prevention of cholangiocarcinoma in primary sclerosing cholangitis.

The influence of demographic and disease-related factors on health-related quality of life in patients with ulcerative colitis.

OBJECTIVE: The aims of this study were to analyse the health-related quality of life of patients with ulcerative colitis and to assess in what way demographic and disease-related factors influence patients' experiences of this, in order to interpret the results of health-related quality of life assessment more correctly. PATIENTS AND METHODS: We carried out a cross-sectional evaluation of 300 consecutive patients with ulcerative colitis from the catchment areas of Linköping University Hospital and Orebro University Hospital in Sweden. Health-related quality of life was measured using four questionnaires: the IBDQ, the RFIPC, the SF-36 and the PGWB. Disease activity was evaluated using a one-week symptom diary, blood tests and rigid sigmoidoscopy. Demographic factors (gender, age, civil status, educational level), disease-related factors (disease duration, disease extent, disease activity) and presence of co-morbidity were obtained. RESULTS: Health-related quality of life was mainly impaired in the psychological and social areas and to a much lesser degree in physical areas. Patients with relapse had significantly more disease-related worries and concerns (the RFIPC), more impaired social functioning (the IBDQ and SF-36), and a lower feeling of well being (the IBDQ, the SF-36 and the PGWB). However, their physical function (SF-36) was no worse than patients in remission. Besides the symptom burden of the current disease, co-morbidity and female gender were associated with a lower health-related quality of life. CONCLUSION: To correctly interpret health-related quality of life assessments, it is necessary to consider co-morbidity and gender distribution in addition to the symptom burden of the disease studied.

Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives.

BACKGROUND & AIMS: Iron overload may be carcinogenic. Patients with hereditary hemochromatosis (HH) are reportedly at a 20-200-fold risk of intrahepatic cancer, but the reported risks for nonhepatobiliary cancers are conflicting. The risk of cancer in heterozygous individuals (estimated allele frequency, 1/10 to 1/20) is unknown. This study aimed to better assess these risks. METHODS: We performed a population-based cohort study of 1847 Swedish patients with HH and 5973 of their first-degree relatives using nationwide, population-based health and census registers. We used standardized incidence ratios (SIRs) as relative risk. RESULTS: With 62 liver cancers and 128 nonhepatobiliary cancers, patients with HH were at a 20-fold risk of liver cancer (SIR, 21; 95% confidence interval [CI], 16-22) but an almost unaltered risk of all other cancers (SIR, 1.2; 95% CI, 1.0-1.4), including nonelevated risks for several gastrointestinal tract cancers. At 10 years of follow-up, the absolute risk of liver cancer was 6% among men and 1.5% among women. With 21 liver cancers and 508 nonhepatobiliary cancers, first-degree relatives were at an unaltered risk of extrahepatic cancer (SIR, 1.0; 95% CI, 0.9-1.1, including unelevated risks for gastrointestinal cancers) but at a modest and historic increased risk of hepatobiliary cancer (SIR, 1.5; 95% CI, 1.0-2.4), the histopathologic spectrum of which differed from the patients. CONCLUSIONS: Patients (particularly men) with HH are at increased risk for hepatocellular cancer, although the magnitude of the risk is lower than previous estimates. Overall cancer risk in first-degree relatives does not seem to be increased.

Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC).

BACKGROUND/AIMS: This study aims at describing the natural history and outcome of small duct primary sclerosing cholangitis (PSC). METHODS: Thirty-two patients with small duct PSC were studied. The average time taken for diagnosis was 69 (1-168) months. The median follow-up time was 63 (1-194) months. RESULTS: All patients including one who underwent liver transplantation because of end-stage liver disease and hepatocellular carcinoma were alive at follow-up. None developed cholangiocarcinoma. In 27 patients repeated cholangiographic examinations were done after a median time of 72 (12-192) months from first ERCP. Four developed features of large duct PSC. CONCLUSIONS: Small duct PSC rarely progresses to large bile duct PSC and it seems to have a benign course in most patients and no development of cholangiocarcinoma was found.

Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.

BACKGROUND/AIMS: To assess the risk of hepatic and extrahepatic malignancies in a large cohort of Swedish primary sclerosing cholangitis (PSC) patients compared with that of the general Swedish population. METHODS: The study cohort comprised 604 PSC patients identified between 1970 and 1998. Follow-up was provided through linkages to the Swedish Cancer and Death registries. Cumulative incidence of malignancies and standard incidence ratio were calculated with the incidence rates in the Swedish population, taking into account: sex, age and calendar year as comparison group. RESULTS: Median time of follow-up was 5.7 years (range 0-27.8). Seventy-nine percent had concomitant inflammatory bowel disease. The cause of death was cancer in 44%. The frequency of hepatobiliary malignancies was 13.3% (81/604). Thirty-seven percent (30/81) of all hepatobiliary malignancies were diagnosed less than 1 year after the diagnosis of PSC. The risk for hepatobiliary malignancy was increased 161 times, for colorectal carcinoma 10 times and for pancreatic carcinoma 14 times, compared with that of the general population. CONCLUSIONS: In this national-based study including the largest cohort of PSC patients ever presented, the frequency of cholangiocarcinoma is 13%. The risk of hepatobiliary carcinoma is constant after the first year after PSC diagnosis with an incidence rate of 1.5% per year. The risk of pancreatic carcinoma is increased 14 times compared with the general Swedish population. These results are suggestive of an increased risk of pancreatic carcinoma in patients with PSC.