[Diagnosis of haemochromatosis]. / Diagnostiek naar hemochromatose.

Interpretation of laboratory parameters in cases of haemochromatosis can be difficult. Here, we describe two patients with markedly elevated transferrin saturation and high ferritin levels. The first patient is a 51-year-old woman who had been complaining of fatigue, abdominal pain and arthritis for three years. Her liver enzymes were mildly elevated. Secondary causes of iron overload had been excluded. DNA investigation found a homozygous p.Cys282Tyr mutation in the HFE protein, consistent with hereditary haemochromatosis. The second patient is a 58-year-old man with general malaise and cholestatic liver injury. The p.Cys282Tyr and p.His63Asp mutations in the HFE protein could not be detected. Ultrasound of the liver revealed steatosis. The patient was a heavy drinker and a diagnosis of iron overload caused by alcoholic liver disease was made. Based on these case reports, we discuss the strategy to diagnose haemochromatosis and the background of associated laboratory tests.

[Recurrent pulmonary embolism due to popliteal venous aneurysm]. / Recidiverende longembolieën bij aneurysma V. poplitea.

BACKGROUND: Popliteal venous aneurysms are very rare, but when left untreated they can lead to severe and recurrent pulmonary embolism. CASE DESCRIPTION: A 35-year-old man was referred to the outpatients' vascular clinic for additional diagnostics of a swelling just above the back of his right knee. He had a history of recurrent idiopathic pulmonary embolism despite anticoagulation. Diagnostic imaging revealed a large popliteal venous aneurysm. The patient underwent surgical resection of the aneurysm and was prescribed oral anticoagulation postoperatively. Duplex ultrasound at 3 months postoperative revealed unimpeded blood flow in the venous interposition graft. The patient no longer had oedema. CONCLUSION: Aneurysms of the popliteal vein should be included in the differential diagnosis of patients with pulmonary embolism. In patients with unexplained recurrent pulmonary embolism despite anticoagulation, additional diagnostic imaging of the lower extremities should be considered and inclusion of duplex ultrasound is recommended.

[A pregnant woman with autoimmune thyroiditis and recurrent goiter]. / Een zwangere met auto-immuunthyreoïditis en recidiverend struma.

A 27-year-old woman was first referred at the age of 14 with cosmetic complaints due to an echographically diffuse, euthyroid goitre. Tests for antibodies against thyroid peroxidase and thyroglobulin were positive. Thyroid-suppression therapy with levothyroxine resulted in regression of the goitre. At the age of 26 there was a transitory recurrence of the goitre during a pregnancy, during which time the thyroid peroxidase antibodies became strongly positive. Six months post partum the goitre recurred again, accompanied by pain in the throat and fever. The C-reactive protein level was strongly elevated. Serology established the diagnosis of viral thyroiditis due to a Coxsackie-B virus. The size of the goitre decreased after treatment with acetylsalicylic acid and prednisone. Two months later the goitre again showed further growth, now in association with cervical lymphadenopathy and an enlarged left parotid gland. Histology revealed a non-Hodgkin lymphoma of the type diffuse large B-cell (stage II), very likely a primary thyroid lymphoma. The lymphoma was refractory to cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP); this was followed by intensive chemotherapy and autologous stem-cell transplantation, resulting finally in a complete remission. The goitre disappeared and thyroid peroxidase antibodies were no longer detectable. Primary thyroid lymphoma is a rare disease, but autoimmune thyroiditis appears to be an important predisposing factor.

[Thrombocytopenia during pregnancy]. / Trombocytopenie tijdens de zwangerschap.

Thrombocytopenia during pregnancy can be caused by a broad variety of disorders. An early diagnosis is essential for timely and adequate therapy. In cases of severe thrombocytopenia, a multidisciplinary approach by a team of obstetricians, haematologists and anaesthesiologists is needed. We describe a 30-year-old patient at a gestational age of 35 weeks who presented with preterm rupture of membranes. Coincidentally, she also had severe thrombocytopenia that proved to be due to immune thrombocytopenia (ITP). The severe thrombocytopenia persisted despite standard first-line treatment with corticosteroids and intravenous immunoglobulins. Based on this case report we discuss the differential diagnosis of thrombocytopenia during pregnancy with a focus on the management of ITP in pregnant women.

Clinical experience with CD3 x CD19 bispecific antibodies in patients with B cell malignancies.

In extensive preclinical testing, a CD3 x CD19 bispecific antibody (BsAb) induced killing of malignant B cells by resting T cells even in an autologous situation. In a 14 day clonogenic assay using a CD19+ pre-B cell line (REH), BsAb required repeated administration together with IL-2 to achieve a 5 log kill by resting peripheral blood T cells. Intravenously administered BsAb in an intrapatient dose escalation study of 3 patients with B cell non-Hodgkin's lymphoma showed limited toxicity (WHO grade II fever and chills) due to tumor necrosis factor-alpha (TNF-alpha) release by T cells. Pharmacokinetics with 2.5 mg BsAb showed peak levels of 200-300 micrograms/ml and a t1/2 of 10.5 h. The next patient, with chronic lymphocytic leukemia (CLL), received 0.6 mg BsAb/m2 as an i.v. infusion preceded by 1 MU IL-2/m2 s.c. Improved T cell activation was noted, as indicated by an increase in IFN-gamma, IL-6, IL-8, and IL-10, in addition to high TNF-alpha increases. TNF-alpha increases were highest on the first day. Toxicity remained restricted to grade II fever and chills, observed every day after the infusion of BsAb. No clear clinical effects were seen in this chemotherapy-resistant CLL patient with a high tumor burden. If subsequent patients also show limited toxicity, treatment of patients with a lower tumor load seems to be warranted to evaluate the efficacy of CD3 x CD19 BsAb therapy.

CD8 T cell activation after intravenous administration of CD3 x CD19 bispecific antibody in patients with non-Hodgkin lymphoma.

A bispecific antibody directed to T and B cells (CD3 x CD19 bsAb) was daily infused intravenously in escalating doses from 10 micrograms up to 5 mg in three patients with chemotherapy-resistant non-Hodgkin lymphoma; in this way we aimed to activate T cells to kill the malignant B cells. Only limited toxicity was observed, consisting of moderate fever preceded by chills or shivers and mild thrombocytopenia. No human anti-(mouse Ig) antibodies were found. Pharmacokinetics showed a t1/2 of 10.5 h with peak levels of 200-300 ng/ml after infusion of 2.5 mg bsAb. bsAb in serum was functionally active in vitro. After bsAb infusion a rise in serum tumour necrosis factor alpha was observed, accompanied by an increase in soluble CD8 and to some extent in soluble interleukin-2 receptor (IL-2R), but not in interferon gamma. IL-4 or soluble CD4. No evidence was found for monocyte activation (no increases in IL-6, IL-8 or IL-1 beta in serum). No gross changes in histology or number of IL-2R+, CD4+ or CD8+ cells were found in the lymph nodes after therapy, but one patient showed activated CD8+ T cells within the tumour nodules. In conclusion, after intravenously administered CD3 x CD19 bsAb only moderate toxicity was found, probably due to CD8+ T cell activation and cytokine release, without CD4+ T cell activation.