Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study.

OBJECTIVES: Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. METHODS: We included 713 patients with BE (≥ 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. RESULTS: After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥ 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). CONCLUSIONS: In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Renal infarction after cocaine abuse: a case report and review.

A 36-year-old male presented with sudden pain in the left lower abdomen caused by a left renal infarction. Cocaine metabolites were found in the urine and a cocaine-induced renal infarction was diagnosed. Cocaine-induced renal infarction is not frequently reported in the literature. Pathophysiologic mechanisms include direct cocaine-induced platelet activation in combination with vasoconstriction and endothelial damage. There is no proven therapy for this complication.

Heterozygous alpha-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review.

Alpha-I antitrypsin (AIAT) is an acute-phase protein that is produced in liver cells. AIAT deficiency is a hereditary disease which is defined by the hepatic production of an abnormal protein that can not be released into the plasma. This leads to deficiency of plasma AIAT and subsequently to an impaired protection against proteases, resulting in pulmonary disease. Accumulation of the abnormal protein in hepatocytes can lead to liver damage. Serum level measurement, phenotyping and liver biopsy can be used for establishing the diagnosis. Homozygous AIAT deficiency can cause neonatal hepatitis; in adults end-stage liver disease, cirrhosis and hepatocellular carcinoma can develop. There are strong arguments to consider heterozygous AIAT deficiency as an important co-factor in the aetiology of chronic liver disease. Studies have shown that AIAT heterozygosity can be considered a modifier for hepatitis C virus, end-stage liver disease, cirrhosis and hepatocellular carcinoma. The accumulation of AIAT in the hepatocytes occurs more profoundly in a diseased liver, and as a consequence it affects the natural course of the liver disease. Therapeutic options include augmentation therapy (infusion of purified human plasma AIAT) in pulmonary disease; in end-stage liver disease liver transplantation is an option. For the future, other interventions such as gene therapy or strategies to inhibit polymerisation are promising.

Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis.

HFE-related hereditary haemochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone hepcidin appears to play a role. Ways of diagnosing iron overload include measurement of the serum iron parameters, i.e. serum transferrin saturation and serum ferritin, by a liver biopsy or by calculating the amount of mobilisable body iron withdrawn by phlebotomies. Clinical signs attributed to HFE-related HH include liver failure, arthralgia, chronic fatigue, diabetes mellitus and congestive heart failure. organ failure can be prevented by phlebotomies starting before irreversible damage has occurred. Therefore, screening to facilitate early diagnosis is desirable in individuals at risk of developing HFE-related iron overload. over time it appeared that the clinical penetrance of the HFE mutations was much lower than had previously been thought. This changed the opinion about a suitable screening modality from case detection, via population screening, to family screening as the most appropriate method to prevent HFE-related disease. However, before the implementation of family screening it is vital to have thorough information on the relevance of the specific health problem involved, on the clinical penetrance of C282Y homozygosity and on the effectiveness of the screening approach.

Morbidity and mortality in first-degree relatives of C282Y homozygous probands with clinically detected haemochromatosis compared with the general population: the HEmochromatosis FAmily Study (HEFAS).

BACKGROUND: Family screening has been suggested as a sophisticated model for the early detection of HFE-related hereditary haemochromatosis (HH). However, until now, controlled studies on the morbidity and mortality in families with HH are lacking. METHODS: Data on iron parameters, morbidity and mortality were collected from 224 dutch C282Y-homozygous probands with clinically overt HH and 735 of their first-degree family members, all participating in the HEmochromatosis fAmily study (HEfAs). These data were compared with results obtained from an age- and gender-matched normal population. HEfAs and controls filled in similar questionnaires on demographics, lifestyle factors, health, morbidity and mortality. RESULTS: A significantly higher proportion of the HEfAs first-degree family members reported to be diagnosed with haemochromatosis-related diseases: 45.7 vs 19.4% of the matched normal population (McNemar p<0.001). Mortality among siblings, children and parents in the HEFAS population was similar to that in the relatives of matched control. CONCLUSION: In this study we show that, morbidity among first-degree family members of C282Y-homozygous probands previously diagnosed with clinically proven HH is higher than that in an age- and gender-matched normal population. Further studies are needed to definitely connect these increase morbidity figures to increase prevalenc of the C282Y mutated HFE-gene and elevated serum iron indices.

[Acute pancreatitis in a hepatitis C positive patient following treatment with peginterferon alfa-2b and ribavirin]. / Acute pancreatitis bij een hepatitis C-positieve patient na behandeling met peginterferon alfa-2b en ribavirine.

A 59-year-old man, treated with peginterferon alfa-2b and ribavirin because of a chronic Hepatitis C virus infection presented in the emergency department with acute epigastric pain. An acute pancreatitis, probably toxic, was diagnosed. A literature search confirmed that acute pancreatitis may develop as a result of treatment with (peg)interferon whether or not in combination with ribavirin. It is important to be aware of pancreatitis when patients treated with these medications present with acute epigastric pain. Discontinuing the medication will lead to a rapid reduction of the symptoms and recovery.

[A man with oral ulcers caused by hypereosinophilic syndrome and a good response to the tyrosine-kinase inhibitor imatinib]. / Een man met orale ulcera door hypereosinofiel syndroom en met een goede respons op de tyrosinekinaseremmer imatinib.

For the last 2 years, a 55-year-old man had painful, recurrent oral ulcers. Histological examination showed non-specific inflammation. Eosinophilia in the blood and bone marrow raised the suspicion of hypereosinophilic syndrome. No other specific organ involvement was observed. The diagnosis was confirmed by detection of the fusion gene 'FIP1-like-1-platelet-derived growth factor receptor alpha' (FIP1L1-PDGFRA) in the peripheral blood and bone marrow. Treatment with the tyrosine-kinase inhibitor imatinib resulted in a rapid response that has been maintained for more than 2 years. Hypereosinophilic syndrome is a rare haematological disorder. Until recently diagnosis was made by exclusion, and the course of disease was often fatal. Fusion of the FIP1L1 gene to the PDGFRA gene was identified recently in some patients with hypereosinophilic syndrome. The fusion results in a novel tyrosine kinase that is constitutively activated and may induce proliferation ofhaematopoietic cells. Treatment with imatinib targets this tyrosine kinase. These advances in our understanding of the molecular biology of the disease will lead to a new classification of hypereosinophilic syndrome with specific therapeutic options.

[Heterozygosity for alpha1-antitrypsin deficiency as a cofactor in the development of chronic liver disease]. / Heterozygotie voor alpha1-antitrypsinedeficiëntie als cofactor bij de ontwikkeling van een chronische leveraandoening.

In 3 patients, 2 men aged 51 and 40 years and a 50-year-old woman, with liver-function disorders due to excessive consumption of alcohol, the liver function deteriorated rapidly resulting in the patients' death. All 3 were found to be heterozygous for alpha1-antitrypsin (AT) deficiency. Alpha1-AT deficiency can lead to cirrhosis of the liver and pulmonary emphysema. There are indications that heterozygous alpha1-AT deficiency can contribute to the development of a chronic liver disease, even when the serum level of alpha1-AT is within the normal range, especially in association with other risk factors such as alcohol abuse or chronic viral hepatitis. Persons with this mutation also have an increased risk for the development of cryptogenic cirrhosis and primary liver-cell carcinoma. Determination of the alpha1-AT phenotype should perhaps be recommended for all patients with a chronic liver disease, especially if the liver function deteriorates more rapidly than expected, even in the presence of a normal alpha1-AT serum level. A liver biopsy remains the gold standard for establishing the presence of alpha1-AT deposits in the liver.

Radioisotopic labels for blood cell survival studies: a review.

The different methods of labeling blood cells, in particular erythrocytes and platelets, for survival studies are reviewed. Besides the technical information about these procedures, attention is also paid to the indications of blood cell survival studies, the effective dose equivalent involved and the interpretation of the resulting data. In the final section the possibilities created by dual-labeling procedures are discussed.

New possibilities in erythrocyte survival studies with the application of a Well-type germanium semiconductor detector.

The application of a Well-type germanium semiconductor detector creates new possibilities in erythrocyte survival studies. Using 51Cr, the effective dose equivalent in a standard procedure can be reduced from approximately 780 to 2 microSv. The properties of the detector, namely, high efficiency and high energy resolution, also enable the application of two or even more radionuclides within one individual. This is demonstrated by some experiments utilizing a novel dual-label technique with 57Co tropolonate and 58Co tropolonate. Although this new dual-label technique needs further investigation, it underlines the potential possibilities of studying certain unanswered but clinically relevant questions in the field of transfusion medicine with the application of a Well-type germanium semiconductor detector.

Chronic hepatitis caused by lisinopril.

ACE inhibitors are used world-wide for treatment of hypertension and cardiac failure; liver damage is a rare but potentially severe side-effect of these drugs. In this case report we describe a patient with chronic liver damage due to lisinopril.

Ursodeoxycholic acid treatment in primary biliary cirrhosis with the emphasis on late stage disease.

We studied the effect of ursodeoxycholic acid in 19 patients with primary biliary cirrhosis, mainly stages III and IV. The dose of UDCA employed was 10-15 mg/kg body weight per day. After 1 yr, 17 patients were still using UDCA, and the mean values of serum alkaline phosphatase, gamma-glutamyltranspeptidase and alanine-aminotransferase had fallen significantly. Serum bilirubin, initially elevated in 7 of the 13 late-stage (III and IV) patients, showed a further increase in 3 of the 7 patients. In 2 of these 3 patients, UDCA had to be withdrawn (dose reduction had no effect). One patient developed a decompensated cirrhosis in spite of UDCA withdrawal. Pruritus worsened in 4 patients, all of whom were late stage patients. Ten late-stage (III-IV) patients showed improvement in liver biochemistry and clinical findings as did all early-stage PBC patients. Thus, UDCA treatment is not beneficial for all PBC patients. Special care should be taken in the early phase of UDCA therapy in later-stage (III-IV) patients: frequent biochemical checks should be carried out, for instance every 2 weeks in the first 2 months after starting UDCA, especially the estimation of bilirubin.

[Diagnostic image (151). A woman with malaise and changed liver enzyme levels]. / Diagnose in beeld (151). Een vrouw met malaise en afwijkende leverenzymwaarden. Adenomatosis hepatis.

In a 41-year-old woman with general malaise and changed liver enzyme levels ultrasonography and MRI revealed hepatic adenomatosis.

[Three patients with weight loss as a result of sarcoidosis presenting as liver disease]. / Drie patiënten met gewichtsverlies door sarcoïdose, zich uitend als leverziekte.

Sarcoidosis presenting as a liver disease is uncommon. Hepatic sarcoidosis was diagnosed in three male patients aged 80, 64 and 69 years. They all presented with aspecific symptoms such as weight loss. Further investigation revealed liver disease, and liver biopsies demonstrated the presence of non-caseating granulomas. However, non-caseating granulomas can be associated with a great number of disorders and are therefore not specific. Other causes were excluded before the diagnosis of hepatic sarcoidosis was established with reasonable certainty. The diagnosis was finally confirmed on the basis of medical history, laboratory tests and histology. Sarcoidosis presenting as symptomatic liver disease can be treated with corticosteroids and probably with ursodeoxycholic acid as well. These three patients were treated with corticosteroids. The first patient died a year later from a cerebral infarct, the second one after a few months from a (non-sarcoidotic) cerebral haemorrhage and the third one after eight years from hepatic failure.

[Immunodeficiency in adult patients as the first sign of a primary underlying condition]. / Immuundeficiëntie bij een volwassen patiënt als eerste manifestatie van een primaire onderliggende ziekte.

Three male patients, aged 56, 40 and 52 years, presented with recurrent infections and clinically suspected immunodeficiency, which was confirmed by the presence of hypogammaglobulinaemia. In one patient, no obvious underlying disease was identifiable, and primary immunodeficiency syndromes were considered in the differential diagnosis. A thorough diagnostic work-up revealed the presence of non-Hodgkin lymphoma in an iliac crest biopsy specimen. The second patient was found to have a thymoma. In the third patient, the immunodeficiency was the key to the ultimate diagnosis of multiple myeloma, which was still asymptomatic at that stage. Establishing the underlying condition had important therapeutic and prognostic consequences in these patients.

[Clinical thinking and decision-making in practice. A pregnant Turkish woman with a liver tumor]. / Klinisch denken en beslissen in de praktijk. Een zwangere Turkse vrouw met een tumor in de lever.

A 30-year-old Turkish woman suffered from pain in the right upper abdomen during the 32nd week of her third pregnancy. On ultrasound a liver tumour was diagnosed. The patient was followed without treatment during pregnancy. The outcome of the pregnancy was uncomplicated. The diagnosis of focal nodular hyperplasia was made post partum using MRI with contrast and a liver biopsy. The born son suffered the syndrome of Klippel-Trenaunay-Weber, also a vascular malformation. A liver tumour during pregnancy can influence the outcome of the pregnancy, but the pregnancy may also affect the progression of tumour growth. Considerations regarding the diagnostic evaluation and treatment should be made with caution. Ultrasound and MRI are well established methods to diagnose a liver tumour during pregnancy. The duration of the pregnancy is important in the diagnostic and therapeutic approach to the tumour.

[Fibrosing mediastinitis: a rare cause of fever]. / Fibroserende mediastinitis: een zeldzame oorzaak van koorts.

A 47-year-old woman was examined due to fever of unknown origin. She had been on holiday in Southeast Asia. Routine laboratory investigations confirmed the presence of inflammation. Serology for Hepatitis B virus, HIV, Borrelia, Cytomegalovirus, toxoplasmosis, lues, Epstein Barr virus, brucellosis, bartonellosis, histoplasmosis and auto-immune factors was negative. CT-scans of the chest and abdomen failed to reveal the cause. Finally, gallium-67 scintigraphy showed an increased uptake in the left mediastinum and the left side of the neck. This led to the discovery of an infraclavicular mass. On histological examination of the surgical excision biopsy the diagnosis 'fibrosing mediastinitis' was made. The patient was treated successfully with corticosteroids.

[Diagnosis of 5 patients with possible primary hemochromatosis]. / Diagnostiek bij 5 patiënten met mogelijk primaire hemochromatose.

In a 49-year-old man and a 28-year-old woman, both of whom complained of fatigue, HFE-gen related respectively non-HFE-gen related primary haemochromatosis was diagnosed, based on the elevated serum transferrin saturation, the elevated serum ferritin levels, DNA studies and liver biopsy with qualitative respectively quantitative iron measurements. Their complaints diminished after bloodletting. Three women respectively 64, 61 and 46 years of age, were also suspected of primary haemochromatosis. The latter two presented with complaints of fatigue and malaise and chronic hepatitis C respectively. All three showed an elevated serum transferrin saturation and serum ferritin concentration. Further investigation showed the presence of secundary iron overload. Causes for it being excessive alcohol consumption, overweight and a poorly regulated diabetes mellitus type 2, and chronic hepatitis C respectively. These patients received specific therapy. Primary haemochromatosis is a common disorder of iron metabolism in individuals of Northern European descent. Diagnosis is based on an elevated serum transferrin saturation in combination with both elevated serum ferritin levels and homozygosity for the Cys282Tyr-mutation in the HFE-gen. The presence of an elevated serum transferrin saturation in combination with an elevated serum ferritin level is not always sufficient for the diagnosis, since these may be affected by other disorders. Moreover, iron overload may be caused by a form of haemochromatosis that is not HFE-related. In case of doubt as to the diagnosis, histological examination of the liver with a qualitative or quantitative iron determination is the golden standard.

[Chronic hepatitis C in hemodialysis patients]. / Chronische hepatitis C bij hemodialysepatiënten.

Hepatitis C virus (HCV) is an important cause of chronic hepatitis in dialysis patients. With regard to epidemiology, the time on haemodialysis, the (previous) use of intravenous drugs as well as the number of blood transfusions received are important risk factors. There are strong indications suggesting nosocomial transmission of HCV. Strict application of infection prevention procedures in haemodialysis units is mandatory to restrain spread of HCV infection. Preliminary results show equal efficacy of alpha-interferon in normalisation of serum transaminases in dialysis patients and in patients with normal kidney function. However, in both groups relapses occur often, despite induction of remission. Antiviral therapy (with interferon and ribavirin) is emerging as a valid option to induce HCV eradication in dialysis patients. Thereafter, transplantation may be considered.

[Primary liver cell carcinoma as complication of alpha 1-antitrypsin deficiency in a 67 year old man]. / Primair levercelcarcinoom als complicatie van alpha 1-antitrypsinedeficiëntie bij een 67-jarige man.

A 67-year-old male patient with pulmonary emphysema was diagnosed with liver cirrhosis. Further investigations revealed an alpha 1-antitrypsin deficiency caused by a PiZZ mutation. The liver cirrhosis was complicated by the development of a hepatocellular carcinoma. The patient died from the consequences of mesentary vein thrombosis. The protease inhibitor alpha 1-antitrypsin controls the tissue damaging effects of proteases which are produced by granulocytes. In the case of alpha 1-antitrypsin deficiency, progressive damage of the lung tissue occurs, resulting in emphysema. The accumulation of abnormal alpha 1-antitrypsin in hepatocytes can result in cirrhosis, with an increased chance of carcinoma. The deficiency is caused by a mutation in the Pi-gene on chromosome number 14. Although treatment options are at present limited, making an early diagnosis has important implications for the prognosis and intended management with respect to the prevention of complications, both in the patient as well as in first degree relatives (children and siblings).