Unexplained Liver Disease Research Articles

The Diagnosis and Management of Alpha-1 Antitrypsin Deficiency in the Adult.

Background: The diagnosis and clinical management of adults with alpha-1 antitrypsin deficiency (AATD) have been the subject of ongoing debate, ever since the publication of the first American Thoracic Society guideline statement in 1989.1 In 2003, the "American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency" made a series of evidence-based recommendations, including a strong recommendation for broad-based diagnostic testing of all symptomatic adults with chronic obstructive pulmonary disease (COPD).2 Even so, AATD remains widely under-recognized. To update the 2003 systematic review and clinical guidance, the Alpha-1 Foundation sponsored a committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD. Purpose: To provide recommendations for: (1) the performance and interpretation of diagnostic testing for AATD, and (2) the current management of adults with AATD and its associated medical conditions. Methods: A systematic review addressing the most pressing questions asked by clinicians (clinician-centric) was performed to identify citations related to AATD that were published since the 2003 comprehensive review, specifically evaluating publications between January 2002 and December 2014. Important, more recent publications were solicited from the writing committee members as well. The combined comprehensive literature reviews of the 2003 document and this current review comprise the evidence upon which the committee's conclusions and recommendations are based. Results: Recommendations for the diagnosis and management of AATD were formulated by the committee. Conclusions: The major recommendations continue to endorse and reinforce the importance of testing for AATD in all adults with symptomatic fixed airflow obstruction, whether clinically labeled as COPD or asthma. Individuals with unexplained bronchiectasis or liver disease also should be tested. Family testing of first-degree relatives is currently the most efficient detection technique. In general, individuals with AATD and emphysema, bronchiectasis, and/or liver disease should be managed according to usual guidelines for these clinical conditions. In countries where intravenous augmentation therapy with purified pooled human plasma-derived alpha-1 antitrypsin is available, recent evidence now provides strong support for its use in appropriate individuals with lung disease due to AATD.

High prevalence of antibodies against hepatitis E virus in HIV-infected patients with unexplained liver disease

ObjectiveTo look for evidence of hepatitis E virus (HEV) exposure in HIV-infected patients with unexplained elevations of liver stiffness (LS). MethodsCase–control study conducted in 31 HIV-infected patients with unexplained elevations of LS and in 31 HIV-controls with normal LS, matched by age, sex and CD4 cell-counts. Serum HEV antibodies were tested by two ELISA procedures and by Immunoblot. We defined exposure to HEV as the detection of serum HEV antibodies by at least one of the two ELISA assays, provided that it was confirmed by Immunoblot. A real-time PCR RNA assay was conducted in all plasma samples to identify subjects with active HEV infection. ResultsExposure to HEV was demonstrated, according to the criteria used in this study, in 9 (29%) of the cases, whereas it was shown in 5 (16%) of the controls (p=.3). Serum HEV RNA was detected in none of the controls and in only in one case. This patient had a documented chronic hepatitis E with progression to cirrhosis. ConclusionsHEV antibodies are frequently found in HIV-infected patients with unexplained liver disease.

MMWR: CDC Guidance for Evaluating Healthcare Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management

MMWR: CDC Guidance for Evaluating Healthcare Personnel for Hepatitis B Virus Protection and for Administering Postexposure Management

Alpha- 1-Antitrypsin Gene Subtypes and the Risk of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is the most prevalent clinical disorder. It is generally considered to be due to an imbalance between proteolytic enzymes and their inhibitors. Deficiency of alpha 1-antitrypsin (α1-AT) is a recognized risk factor for COPD and is characterized by the progressive obstruction of airways, which is not fully reversible. Alpha-1-antityrpsin deficiency is widely under-diagnosed in many populations with majority of the individuals remaining undetected due to the delay in the onset and variability of respiratory symptoms. In 1997, WHO stated that 2–3% of all alpha-1-antitrypsin deficient individuals were homozygous for PiZ and recommended screening for α1-AT deficiency in individuals with COPD, all adults and adolescents with asthma as well as neonates, children and adults with unexplained liver disease.

Analysis of clinical and biochemical spectrum of Wilson Disease patients

Wilson disease (WD) is autosomal recessive disorder of copper metabolism. Wilson disease patients usually suffer from hepatic or neuropsychiatric complications. The symptoms appear between ages five to 35 but it can vary from two years to 72 years. Study was carried out from June 2008 to November 2010. This study included nine families with eleven cases of WD to determine clinical presentation, diagnostic findings (including laboratory results) and liver histology. It included 11 patients who presented with hepatic manifestations and/or Neuropsychiatric manifestations and/or family history suggesting features of WD. Patients with hepatitis B and C and those with history of taking antipsychotic drugs were excluded from the study. Patient's data was included in a well designed performa. Liver function test, serum ceruloplasmin, serum copper, 24 hour urinary copper, blood complete picture were analyzed. Quantitative data such as age, hemoglobin etc were expressed as mean with ± SD and quantitative variables such as sex, movement disorders, hepatic involvement etc were expressed as frequency and percentage. There were five male and six female patients with evidence of various manifestations here (i) hepatic in which they had only liver dysfunction (ii) hepatic and neurological (iii) neurological. The mean age of presentation was 8.7±3.92 years (range 4-19 years) and 45% were male patients. Decreased serum ceruloplasmin, enhanced 24-h urinary copper excretion and signs of chronic liver damage were confirmed in all patients and Kayser-Fleischer rings (KF rings) in 72% of patients. In severe WD patients, serum prothrombin activity was less than 50%, serum ceruloplasmin were low and serum copper levels were high than those in non-severe WD patients. High degree of suspicion leads to early treatment with good outcome. The WD is rare but important cause of chronic liver disease. Clinical and biochemical analysis in cases of patients with unexplained liver disease with high degree of suspicion can lead to early treatment with good outcome.

Lymphangiome kystique médiastinal solitaire (LKM)

OBJECTIVE:LKM-positive, or type 2, autoimmune hepatitis is characterized by the presence of antibodies directed against liver–kidney microsomes (LKM1). Although described frequently in southern Europe and the Mediterranean, this subtype of autoimmune liver disease seems to be extremely rare in northern Europe and in the United States. We report here five cases of LKM-positive autoimmune hepatitis that were seen at our center in the period 1989–1999.METHODS:We reviewed the medical records of all patients with the diagnosis of AIH in our institution during the period 1989–1999, and found that five patients had type 2 AIH. All patients were female; four of five were young, and four of five presented with overt cirrhosis.RESULTS:One patient died, one underwent liver transplantation and two are currently awaiting liver transplantation. Response to conventional immunosuppressive therapy was poor and two patients required treatment with cyclosporine and tacrolimus respectively. Four of five patients had at least one associated autoimmune disorder, including IgE-induced IgA deficiency, idiopathic thrombocytopenic purpura (ITP), and arthritis. HLA class II DR4 was present in two patients.CONCLUSIONS:LKM-positive autoimmune hepatitis seems to be a subset of autoimmune hepatitis with distinct clinical features; although rare, it is occasionally encountered in the western United States. Prompt diagnosis and appropriate immunosuppressive treatment are recommended, as well as early referral to transplantation centers. Clinicians should be aware of this condition in the setting of young female patients with unexplained severe liver disease.

Identifications of polyphyletic variants in acute hepatitis suggest an underdiagnosed circulation of hepatitis E virus in Argentina

Background In recent years, an increasing number of infections with genotype 3 hepatitis E virus (HEV) have been reported in western countries. Data in South America, however, are still scarce. Swine and human variants previously described in Argentina are closely related to a human Austrian one. Objective To identify whether HEV is still circulating in Argentina. Study design Sera and stool samples from adults and children with unexplained acute liver disease referred to our center during the last six years were prospectively studied. Dual infection with hepatitis A was retrospectively studied in a group of children with fulminant hepatic failure. Results Fifteen new cases (13 adults and 2 children), seven of whom required hospitalization, were diagnosed. Nine had detectable HEV RNA, and one had imported genotype 1. Subgenotype 3i HEV-related variants are still circulating. Five autochthonous sequences, related to European, American and Japanese ones, grouped in subgenotype 3a. One case had a subgenotype 3b variant. Discussion The polyphyletic variants widespread in Argentina suggest multiple sources of infection. Whether or not their reservoir is swine merits further investigation. Since hepatitis E is still considered rare, differential laboratory testing in unexplained acute liver disease is not routinely performed in Argentina. Broadening awareness of this disease is important in light of the decrease in hepatitis A incidence since universal vaccination was implemented in 2005. The diagnosis of hepatitis E with a combination of serological and molecular tools is needed to better understand its epidemiology and impact on the clinical management of patients with unexplained increased transaminases.

Alpha1-antitrypsin deficiency: a clinical-genetic overview.

Severe α1-antitrypsin deficiency (AATD) is an inherited disorder, leading to development of emphysema in smokers at a relatively young age with disability in their forties or fifties. The emphysema results from excessive elastin degradation by neutrophil elastase as a result of the severe deficiency of its major inhibitor α1-antitrypsin (AAT). The AAT expression is determined by the SERPINA1 gene which expresses codominant alleles. The three most common alleles are the normal M, the S with plasma levels of 60% of normal, and the severely deficient Z with levels of about 15% of normal. Homozygosity for the Z mutant allele is associated with retention of abnormal AAT in the liver, which may lead to neonatal hepatitis, liver disease in children, and liver disease in adults. Regular intravenous infusions of purified human AAT (AAT augmentation therapy) have been used to partially correct the biochemical defect and protect the lung against further injury. Two randomized controlled trials showed a trend of slower progression of emphysema by chest computerized tomography. Integrated analysis of these two studies indicated significantly slower progression of emphysema. AAT is quantified by immunologic measurement of AAT in serum, the phenotype characterized by isoelectric focusing, the common genotypes by targeted DNA analysis, and by sequencing the coding region of the gene when the AAT abnormality remains undefined. AATD is often unrecognized, and diagnosis delayed. Testing for AATD is recommended in patients with chronic irreversible airflow obstruction, especially in those with early onset of disease or positive family history. Testing is also recommended for immediate family members of those with AATD, asthmatics with persistent airflow obstruction, and infants and older subjects with unexplained liver disease. There are over 100 different AAT gene variants; most are rare and only some are associated with clinical disease.

Alpha-1-Antitrypsin Deficiency Initially Presenting in an Adult Surgical Patient: A Case Report and Review of Current Understanding of Disease Process

Alpha-1-antitrypsin (AAT) is one of several serpin molecules which functions to balance the action of various endogenous proteolytic enzymes. A deficiency of functional levels of this enzyme is most commonly inherited in an autosomal recessive fashion. Greater than 95% of AAT-deficient persons are homozygous for the non-functional Z-variant of the enzyme. ZZhomozygosity is relatively common, affecting 1 in 2500 persons of northern European decent. Known complications of AATdeficiency include early-onset emphysema, childhood liver disease, cirrhosis, and increased incidence of hepatocellular carcinoma. Although AAT-deficiency is frequently diagnosed in early childhood, it is not uncommon for persons to go undiagnosed for many years until otherwise unexplained lung or liver disease become evident. We report a case of AATdeficiency in a 44-year-old female which became evident post-operatively after unexplained, uncontrollable ascites and respiratory failure.

Alpha-1-Antitrypsin Deficiency Initially Presenting in an Adult Surgical Patient: A Case Report and Review of Current Understanding of Disease Process

Alpha-1-antitrypsin (AAT) is one of several serpin molecules which functions to balance the action of various endogenous proteolytic enzymes. A deficiency of functional levels of this enzyme is most commonly inherited in an autosomal recessive fashion. Greater than 95% of AAT-deficient persons are homozygous for the non-functional Z-variant of the enzyme. ZZhomozygosity is relatively common, affecting 1 in 2500 persons of northern European decent. Known complications of AATdeficiency include early-onset emphysema, childhood liver disease, cirrhosis, and increased incidence of hepatocellular carcinoma. Although AAT-deficiency is frequently diagnosed in early childhood, it is not uncommon for persons to go undiagnosed for many years until otherwise unexplained lung or liver disease become evident. We report a case of AATdeficiency in a 44-year-old female which became evident post-operatively after unexplained, uncontrollable ascites and respiratory failure.

291 Monitoring Peripheral Blood CD4+ Adenosine Triphosphate (ATP) Activity in Orthotopic Liver Transplantation (OLT) Recipients with Hepatitis C Virus (HCV) Infection and Its Correlation to Fibrosis Progression

liver disease from other etiologies (hepatitis B or C, alcohol abuse or iron overload). Toxicants were included in the analysis if 60% or more of subjects had detectable levels. We ended up with 116 toxicants in the analysis. Subjects were stratified by toxicant level into quartiles and the odds ratio for abnormal ALT was determined after adjusting for confounding variables like age, sex, race, BMI, and insulin resistance (HOMA score) using logistic regression analysis. Results: 4582 subjects were included in the analysis. Of these, 34.1% were found to have abnormal ALT. Several organochlorine pesticides (or metabolites) including dieldrin, oxychlordane, trans-nonachlor, and heptachlor epoxide were associated with a dose-dependent increased risk for ALT elevation. Among heavy metals, lead, mercury, and thallium also demonstrated a dose-dependent increased risk for ALT elevation. Conclusions: In the US population, exposures to specific organochlorine pesticides and heavy metals are associated with a dose-dependent increased risk for otherwise unexplained liver disease. Although most of these organochlorine pesticides are no longer used, they are persistent pollutants which appear to be clinically relevant. The pathogenic role of these toxicants in liver diseases such as NAFLD should be explored. Acknowledgement: The authors would like to acknowledge the AASLD Sheila Sherlock Award (Cave), NIH (McClain), and the National Institute of Environmental Health Sciences (P30ES01444301A1) (Brock) for their support of this research.

290 Cumulative Incidence and Risk Factors of Hepatocellular Carcinoma (HCC) in Patients with END-Stage Liver Disease Secondary to Nonalcoholic Steatohepatitis (NASH)

liver disease from other etiologies (hepatitis B or C, alcohol abuse or iron overload). Toxicants were included in the analysis if 60% or more of subjects had detectable levels. We ended up with 116 toxicants in the analysis. Subjects were stratified by toxicant level into quartiles and the odds ratio for abnormal ALT was determined after adjusting for confounding variables like age, sex, race, BMI, and insulin resistance (HOMA score) using logistic regression analysis. Results: 4582 subjects were included in the analysis. Of these, 34.1% were found to have abnormal ALT. Several organochlorine pesticides (or metabolites) including dieldrin, oxychlordane, trans-nonachlor, and heptachlor epoxide were associated with a dose-dependent increased risk for ALT elevation. Among heavy metals, lead, mercury, and thallium also demonstrated a dose-dependent increased risk for ALT elevation. Conclusions: In the US population, exposures to specific organochlorine pesticides and heavy metals are associated with a dose-dependent increased risk for otherwise unexplained liver disease. Although most of these organochlorine pesticides are no longer used, they are persistent pollutants which appear to be clinically relevant. The pathogenic role of these toxicants in liver diseases such as NAFLD should be explored. Acknowledgement: The authors would like to acknowledge the AASLD Sheila Sherlock Award (Cave), NIH (McClain), and the National Institute of Environmental Health Sciences (P30ES01444301A1) (Brock) for their support of this research.

Diagnosis and Quantitation of Fibrosis

Hepatic fibrosis is the final common pathway for many different liver insults. Originally considered to be irreversible, hepatic fibrosis is now known to be a dynamic process with a significant potential for resolution. The diagnosis and quantitation of fibrosis have traditionally relied on liver biopsy. However, there are a number of drawbacks including the invasive nature of the procedure, sampling error, and interobserver variability. This article reviews the current role of liver biopsy in the assessment of hepatic fibrosis and discusses the role of the newer noninvasive methods including serum markers and radiologic tests.

Antiretroviral-Associated Portal Hypertension: A New Clinical Condition? Prevalence, Predictors and Outcome

Cases of severe unexplained liver disease in HIV-infected individuals have recently been reported and are often associated with exposure to didanosine (ddl) and nodular regenerative hyperplasia. Herein, we examine the clinical outcome following ddl removal. From 3,300 HIV-infected patients attending three clinics since 2004, all who exhibited persistently elevated aminotransferases and/or significant liver fibrosis in the absence of any known cause of liver damage were identified. Thirty-two individuals (prevalence approximately 1%) met the inclusion criteria - all were on antiretroviral therapy. Of these, 84% were male and 68% had acquired HIV through homosexual contact. Liver biopsy was performed in 12, of whom three showed nonspecific advanced liver fibrosis, two nodular regenerative hyperplasia and three showed only periportal fibrosis. On follow up, nine patients developed episodes of hepatic decompensation, mainly as a consequence of portal hypertension; in eight cases (25%) portal thrombosis was diagnosed. No association was found with plasma HIV RNA or CD4+ T-cell count. All patients but three had been exposed to ddl for a median of 44 months; removal of ddl in 27 was followed 12 months later by improvement in clinical and laboratory parameters in 13 (48%) patients. Finally, a trend towards liver fibrosis improvement was recognised using FibroScan. Idiopathic persistent liver enzyme elevations in HIV-infected individuals are often associated with cirrhotic and non-cirrhotic portal hypertension. Although this is a relatively rare condition, prolonged exposure to ddl seems to play a pathogenic role and removal of the drug is associated with clinical and laboratory improvements.

Unexpectedly high incidence of indigenous acute hepatitis E within South Hampshire: Time for routine testing?

Hepatitis E indigenous to developed countries (hepatitis EIDC) is a form of hepatitis E in persons with no travel history to highly endemic areas. It has been recognized recently as an emerging clinical entity in a significant number of economically developed countries including UK. However, it is still perceived as a rare disease and routine laboratory testing for hepatitis E is not performed. A series of 13 cases of hepatitis EIDC, diagnosed in a 13-month period from June 2005 within a single center in South Hampshire, UK, is presented. These patients were identified after implementing a novel-screening algorithm that introduced routine hepatitis E serological investigations. Patients were middle aged or elderly and males were affected more commonly. Four patients (31%) required hospital admission. All reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed cases carried hepatitis E virus (HEV) genotype-3, which bore close sequence homology to HEV circulating in UK pigs. None of these patients recalled eating undercooked pork products or close contact with pigs during the 2 months preceding the onset of acute hepatitis. In comparison, during the same period, only two cases of hepatitis A and five cases of acute hepatitis B were diagnosed. These data illustrate the importance of introducing routine hepatitis E testing in all patients with unexplained acute liver disease and absence of relevant travel history. Routine testing can clarify hepatitis E epidemiology whilst improving the clinical management of patients with acute liver disease.

Doctor, my son is so tired… about a case of hereditary fructose intolerance

We present the case of a 17-year-old male who was diagnosed at birth with hereditary fructose intolerance (HFI). The patient complained of morning-time asthenia and post-prandial drowsiness despite a correct sleep pattern. The physical examination and biological check-up only showed severe vitamin C deficiency (< 10mol/l; normal range: 26–84). The patient's tiredness was attributed to this vitamin C deficiency, which is a frequent side-affect of the fructose-free diet. A change in diet associated with a supplementation in vitamin C was advised, with an increase in vegetable intake, principally avoiding carrots, onions, leaks and tinned sweet-corn. This case offers the opportunity for a review of this rare disease. Two kinds of fructose metabolism disorders (both autosomal recessive) are recognized: 1) essential fructosuria caused by a deficiency of fructokinase, which has no clinical consequence and requires no dietary treatment; 2) HFI, linked to three main mutations identified in aldolase B gene that may be confirmed by fructose breath test, intravenous fructose tolerance test, and genetic testing. In HFI, fructose ingestion generally induces gastro-intestinal (nausea and vomiting, abdominal pain, meteorism) and hypoglycemic symptoms. Fasting is well tolerated. If the condition remains undiagnosed, it leads to liver disease with hepatomegaly, proximal tubular dysfunction, and slow growth and weight gain. In conclusion, endocrinologists should be aware of this rare metabolic disease in order to provide careful follow-up, particularly important when the patient reaches adulthood. Moreover, hypoglycemia induced by fructose absorption, unexplained liver disease, irritable bowel syndrome or familial gout in an adult is suggestive of the diagnosis.

Unexpected diagnosis of cystic fibrosis at liver biopsy: a report of four pediatric cases

We report here four cases of pediatric patients in whom the diagnosis of cystic fibrosis was made only after the histological examination of a liver specimen obtained by biopsy (three cases) or at autopsy (one case). There were two boys and two girls, aged 13 months to 7.5 years. None had a personal or familial history suggestive of cystic fibrosis. One patient, presenting with myocardial lesion and hepatomegaly, died of heart failure; at autopsy, the liver showed a typical aspect of focal biliary cirrhosis. In the three other cases, liver disease was the only manifestation of cystic fibrosis at the time of diagnosis. Liver biopsy examination showed focal biliary cirrhosis in one case and massive steatosis in two. In all four cases, the diagnosis was confirmed by the existence of known pathogenic mutations in the CFTR gene. The evolution was variable; one patient had progressive liver disease with severe portal hypertension after 7 years; another one had lung complications after 1 year. In conclusion, our experience recalls that the diagnosis of cystic fibrosis must be considered in children presenting with unexplained liver disease; its confirmation by molecular techniques makes it possible to set up an appropriate follow-up.

Prevalence of Cholesteryl Ester Storage Disease

Cholesteryl ester storage disease (CESD) is an autosomal recessive chronic liver disease caused by lysosomal acid lipase (LAL) deficiency. The gene is located on chromosome 10q23.2-q23.3, and the enzyme is essential for triglycerides and cholesteryl ester hydrolysis in lysosomes. CESD is characterized by hypercholesterolemia, hypertriglyceridemia, HDL deficiency, and abnormal lipid deposition in many organs. In the liver this results in hepatomegaly caused by hepatic steatosis and fibrosis that can lead to micronodular cirrhosis.1 Disease onset takes place during childhood or adolescence. Males and females are affected in about equal numbers. Patients rarely reach the age of 30. Biochemically, the disorder is recognized by largely reduced lysosomal acid lipase activity.2,3 Complete absence of LAL activity causes Wolman Disease, which is normally fatal within the first 6 months of life.1,4 Several groups have identified mutations in the LAL gene underlying CESD and Wolman disease.5–9 Mutations causing Wolman disease produce an enzyme with no residual activity or no enzyme at all, whereas CESD-causing mutations encode for LAL which retains some enzyme activity.4,10 A G-to-A transition at position −1 of the exon 8 splice donor (E8SJM, E xon 8 S plice J unction M utation) leads to an in-frame deletion of exon 8. The resulting protein is 24 amino acids shorter and has no residual LAL activity, however E8SJM does not cause Wolman Disease because 2% to 4% of normally spliced LAL is present in homozygote carriers.11,12 The vast majority of CESD …

Late onset of Wilson??s disease in a family with genetic haemochromatosis

We report the coexistence of Wilson's disease and genetic haemochromatosis in one family. The diagnosis of genetic haemochromatosis was established in a 52-year-old man. Among his siblings, one 57-year-old sister and one 55-year-old brother had decreased copper and ceruloplasmin levels in serum and increased urinary copper excretion. The sister shared the same human leucocyte antigen haplotypes and was homozygous for the HFE mutation C282Y, like the propositus. However, she had normal liver iron content and increased liver copper content. Her dietary copper intake was probably excessive. The association of Wilson's disease and genetic haemochromatosis is rare and has only been described twice. The onset of Wilson's disease after 50 years of age is rare; Wilson's disease should be considered in any patient with unexplained chronic liver disease; an excess in liver copper content might be induced by excessive dietary input in a susceptible individual.

Screening in liver disease

A disease is suitable for screening if it is common, if the target population can be identified and reached and if both a good screening test and an effective therapy are available. Of the most common liver diseases only viral hepatitis and genetic hemochromatosis partially satisfy these conditions. Hepatitis C is common, the screening test is good and the therapy eliminates the virus in half of the cases, but problems arise in the definition of the target population. In fact generalized population screening is not endorsed by international guidelines, although some recommend screening immigrants from high prevalence countries. Opportunistic screening (case finding) of individuals with classic risk factors, such as transfusion before 1992 and drug addiction, is the most frequently used strategy, but there is disagreement whether prison inmates, individuals with a history of promiscuous or traumatic sex and health care workers should be screened. In a real practice setting the performance of opportunistic screening by general practitioners is low but can be ameliorated by training programs. Screening targeted to segments of the population or mass campaigns are expensive and therefore interventions should be aimed to improve opportunistic screening and the detection skills of general practitioners. Regarding genetic hemochromatosis there is insufficient evidence for population screening, but individual physicians can decide to screen racial groups with a high prevalence of the disease, such as people in early middle age and of northern European origin. In the other cases opportunistic screening of high risk individuals should be performed, with a high level of suspicion in case of unexplained liver disease, diabetes, juvenile artropathy, sexual dysfunction and skin pigmentation.