Diagnostic and therapeutic strategies for porphyrias.

Porphyrias are rare metabolic disorders. Lack of awareness and knowledge about the clinical features of porphyrias results in diagnostic and therapeutic delays for many patients. Delays in diagnosing and treating porphyrias can result in severe, progressive morbidity (and mortality) and psychological distress for patients. This review discusses the pathophysiology, diagnosis, treatment, and follow-up of the most prevalent porphyrias: acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria.

Validation of the 1 µg short synacthen test: an assessment of morning cortisol cut-off values and other predictors.

BACKGROUND: Clinical practice shows that many low-dose short synacthen tests (LD-SSTs) for diagnosing adrenal insufficiency in an outpatient setting have a normal outcome and could be considered superfluous. The objective of this study is to provide a guideline to safely reduce the number of unnecessarily performed LD-SSTs. METHODS: Data of LD-SSTs performed in outpatients were collected. Optimal morning cortisol cut-off values were determined using ROC analysis. Subsequently the predictive value of several variables was tested using univariable and multivariable logistic regression analyses. RESULTS: A morning cortisol lower cut-off value of 145 nmol/l (specificity 89.9%, positive predictive value 90.0%) and an upper cut-off value of 375 nmol/l (sensitivity 100.0%, negative predictive value 100.0%) were found. Chronic fatigue symptoms and symptoms of hypotension or orthostasis as the main reason for performing the test predict a normal outcome. The use of glucocorticosteroids predicts an abnormal outcome of the LD-SST. Oral, topical, nasal and inhaled glucocorticosteroids are each significant predictors when analysed specifically for predicting central adrenal insufficiency. CONCLUSION: By using morning cortisol cut-off values of 145 nmol/l and 375 nmol/l instead of the conventional cut-off values, the number of LD-SSTs performed in an outpatient setting can be reduced by 12%, while maintaining high sensitivity and specificity. Furthermore, the outcome of the LD-SST can be predicted by additional variables such as the indication for performing the test and the use of glucocorticosteroids. Different routes of administration of glucocorticosteroids such as inhalation or topical use should be taken into account when central insufficiency is suspected.

Sex hormone binding globulin deficiency due to a homozygous missense mutation.

CONTEXT: SHBG is known as the major sex steroid binding protein in plasma, and it regulates the bioavailability of both T and estradiol levels required for effects on target tissues. We identified a man with an undetectable SHBG concentration in combination with low total T. He presented with a 7-year history of muscle weakness, fatigue, and a low libido. OBJECTIVES: To determine the cause of the SHBG deficiency, we employed both genetic analysis of the SHBG gene and transgene SHBG expression. RESULTS: Genetic analysis identified a novel homozygous missense mutation that was predicted to be deleterious for protein function. Transgene expression showed that the mutation resulted in a block in SHBG secretion accompanied by increased expression of the endoplasmic reticulum molecular chaperone HSPA5. The mutation results in accumulation of the mutant SHBG within the cell and failure to secrete the mutant protein. Screening of family members identified one sister who was also deficient for SHBG. CONCLUSIONS: We have identified a family with a missense mutation within the SHBG gene, which results in a complete deficiency of plasma SHBG in the homozygous state. Although total T level was low in the male patient, it did not interfere with normal gonadal development and spermatogenesis, suggesting a limited role of SHBG in sexual maturation and male physiology.

[Unexplained anaemia in men: be aware of hypogonadism]. / Onverklaarde anemie bij mannen: denk aan hypogonadisme.

Unexplained anaemia is not uncommon. We present two male patients suffering from longstanding mild anaemia, for which no cause could be found. We performed an extensive analysis, but there were no signs of malignant disease, chronic inflammation, renal failure, hypothyroidism, myelodysplastic syndrome, haemolysis or nutritional deficiencies. However, both patients had symptoms of hypogonadism, confirmed by biochemical testing. The 56-year-old man known with metabolic syndrome turned out to have secondary hypogonadism without a pituitary tumour and the 75-year-old man had primary hypogonadism. After exclusion of prostate carcinoma, testosterone substitution therapy was started in both patients, which improved their haematocrits and sexual and general well-being substantially. Testosterone exerts anabolic effects in multiple organ systems; in bone marrow it potentiates the stimulatory effect of erythropoietin on erythropoiesis. Primary hypogonadism frequently occurs in elderly patients, while secondary hypogonadism is frequently seen in middle-aged men with type 2 diabetes mellitus and obesity.

Alpha lipoic acid: a new treatment for neuropathic pain in patients with diabetes?

BACKGROUND: Neuropathic pain is difficult to treat. We identified those studies in the literature in which the effectiveness of alpha lipoic acid as a treatment for neuropathic pain was evaluated. METHODS: Systematic literature review. The databases MEDLINE and EMBASE were searched using the keywords 'lipoic acid', 'thioctic acid', 'diabet*', and the medical subject headings (MeSH ) 'thioctic acid' and 'diabetes mellitus'. Randomised placebo-controlled trials (RCTs) and meta-analyses were selected and assessed for their methodological quality. RESULTS: Five RCTs and one meta-analysis were found. The Total Symptom Score (TSS) was used as the primary outcome measure. A significant improvement in the TSS was reported in four of the RCTs. An oral or intravenous alpha lipoic dose of at least 600 mg per day resulted in a 50% reduction in the TSS. However, compared with the control group, the TSS reduction in most groups was less than 30%, which is the threshold presumed to be clinically relevant. Four RCTs were of good quality (level of evidence 1b), one RCT had methodological limitations (level 2b), and the methodological quality of the meta-analysis was insufficient for the purposes of this review. CONCLUSION: Based on the currently available evidence, when given intravenously at a dosage of 600 mg once daily over a period of three weeks, alpha lipoic acid leads to a significant and clinically relevant reduction in neuropathic pain (grade of recommendation A). It is unclear if the significant improvements seen after three to five weeks of oral administration at a dosage of >or= 600 mg daily are clinically relevant.

Antithyroid drug regimens before and after 131I-therapy for hyperthyroidism: evidence-based?

BACKGROUND: In view of the new national guideline on thyroid dysfunction, the evidence base for current practice as well as the new guideline is assessed with regard to the use of antithyroid drugs (ATDs) before and after radioiodine (131I) therapy. METHODS: In December 2006, we surveyed 16 hospitals by telephone about different aspects of their antithyroid drug regimen: all eight academic centres and eight nonacademic teaching hospitals. The literature was searched for an evidence-based answer to each question in the inquiry. RESULTS: 13 of 16 hospitals (81%) use antithyroid drugs for pretreatment before 131I. ATDs are discontinued on average four days before 131I or diagnostic scan. However, 27% stop only three days beforehand, which may diminish the effect of 131I. Propylthiouracil (PTU) is also withdrawn four days before 131I, although the literature shows that PTU diminishes the effect of 131I even if it is stopped 15 days beforehand. Resumption of ATDs after 131I to prevent thyrotoxicosis is common practice (81%). One hospital (6%) never restarts ATDs, two (13%) only by indication. Adjunctive treatment consists of combination therapy in 93%, is usually resumed within two days after 131I therapy, and then continued for two to six months. Routine adjunctive treatment is not evidence-based and may be limited to a high-risk subset, especially elderly patients (>70 years) and patients with cardiac comorbidity. Resumption of ATDs within five to seven days after 131I may diminish the effect of 131I. CONCLUSION: Antithyroid drug regimens in the Netherlands are heterogeneous. The evidence base of current practice and the new guideline are discussed.

Oxybutynin: dry days for patients with hyperhidrosis.

We report the case of a 56-year-old postmenopausal woman who was referred to our Endocrinology Outpatient Clinic because of severe hyperhidrosis. She had a four-year history of excessive sweating of her face and upper body. On presentation no sweating could be documented. Physical examination was also unremarkable. It appeared that five days earlier her general practitioner had prescribed oxybutynin for urge incontinence and this accidentally cured her hyperhidrosis. She was diagnosed with idiopathic hyperhidrosis. We advised her to continue the oxybutynin and six months later, she was still symptom-free. Oral anticholinergic drugs are known to be effective for hyperhidrosis, but only anecdotal reports on oxybutynin can be found in the literature. Oxybutynin is not approved for hyperhidrosis, explaining the unfamiliarity with this medicine. This case shows that oxybutynin can be a very effective and simple treatment with only mild side effects. Therefore, oxybutynin merits consideration in patients with idiopathic hyperhidrosis. This report includes a concise review of the causes and treatment options of hyperhidrosis.

Sepsis and elevated liver enzymes in a patient with inflammatory bowel disease: think of portal vein thrombosis.

A 42-year old man, 1 year previously diagnosed with ulcerative colitis after an emergency subtotal colectomy with formation of an ileostomy because of severe colitis with perforation, was admitted with sepsis and jaundice. The liver enzymes were elevated and blood cultures were positive for Streptococcus milleri. Magnetic resonance imaging showed a complete thrombosis of the main stem of the portal vein with occlusion of the left branch. Intravenous antibiotic therapy combined with heparinisation led to complete recanalisation of the thrombus. Portal vein thrombosis is a rare complication of inflammatory bowel disease and has been described in only 10 patients thus far. Multiple aetiologic factors may be responsible in relation to inflammatory bowel disease, such as hypercoagulability, thrombocytosis and abdominal sepsis. In patients with inflammatory bowel disease, unexplained sepsis and abnormal liver function tests, the possibility of an acute portal vein thrombosis should be considered and investigated, because unrecognised it may have serious long-term complications.

[Gallstones following considerable weight loss and recommendations for their prevention]. / Galstenen na forse gewichtsreductie en aanbevelingen ter preventie.

Obesity is an increasing public health problem. As a consequence, many people attempt to lose weight by dieting or participation in weight loss programmes. Weight loss is associated with an increased risk of symptomatic gallstones. Preventive measures include keeping the rate of weight loss below 1.5 kg per week, and providing a fat intake of at least 7 g a day. If it is expected that the rate of weight loss will be faster or difficult to control, for example after bariatric surgery, prophylaxis with ursodeoxycholic acid may be considered.

Macronodular adrenocortical hyperplasia in a postmenopausal woman.

This case report describes the diagnosis of Cushing's syndrome due to macronodular adrenal hyperplasia in an elderly woman who presented with fatigue, muscle weakness and oedema, and recent excessive bruising. Long-standing disease and comorbidity precluded adrenalectomy. Despite treatment with metyrapone and diuretics, the patient died after two months hospitalisation. Postmortal examination revealed overexpression of luteinising hormone (LH) receptors in the adrenal glands, suggesting that the postmenopausal rise in LH may have a role in adrenal hyperplasia and hypercortisolism.

How morphometric analysis of metastatic load predicts the (un)usefulness of PET scanning: the case of lymph node staging in melanoma.

BACKGROUND: In primary cutaneous melanoma, the sentinel node (SN) biopsy is an accurate method for the staging of the lymph nodes. Positron emission tomography (PET) has been suggested as a useful alternative. However, the sensitivity of PET may be too low to detect SN metastases, which are often small. AIM: To predict the value of PET for initial lymph node staging in melanoma based on morphometric analysis of SN metastatic load, without exposing patients to PET. MATERIALS AND METHODS: In 59 SN positive patients with melanoma, the sizes of tumour deposits in the SNs and subsequent dissection specimens were measured by morphometry and correlated with the detection limits of current and future PET scanners. RESULTS: The median tumour volume within the basin was 0.15 mm(3) (range, 0.0001-118.86). Seventy per cent of these deposits were smaller than 1 mm(3). State of the art PET scanners that have a resolution of about 5 mm would detect only 15-49% of positive basins. Logistic regression analysis revealed no pretest indicators identifying patients expected to have a positive PET. However, the SN tumour load was a significant and single predictor of the presence of PET detectable residual tumour. CONCLUSION: Morphometric analysis of metastatic load predicts that PET scanning is unable to detect most metastatic deposits in sentinel lymph nodes of patients with melanoma because the metastases are often small. Therefore, the SN biopsy remains the preferred method for initial regional staging.

Rapid evaluation of FDG imaging alternatives using head-to-head comparisons of full ring and gamma camera based PET scanners--a systematic review.

AIM: While FDG full ring PET (FRPET) has been gradually accepted in oncology, the role of the cheaper gamma camera based alternatives (GCPET) is less clear. Since technology is evolving rapidly, "tracker trials" would be most helpful to provide a first approximation of the relative merits of these alternatives. As difference in scanner sensitivity is the key variable, head-to-head comparison with FRPET is an attractive study design. This systematic review summarises such studies. METHODS: Nine studies were identified until July 1, 2000. Two observers assessed the methodological quality (Cochrane criteria), and extracted data. RESULTS: The studies comprised a variety of tumours and indications. The reported GC- and FRPET agreement for detection of malignant lesions ranged from 55 to 100%, but with methodological limitations (blinding, standardisation, limited patient spectrum). Mean lesion diameter was 2.9 cm (SD 1.8), with only about 20% < 1.5 cm. The 3 studies with the highest quality reported concordances of 74-79%, for the studied lesion spectrum. Contrast at GCPET was lower than that of FRPET, contrast and detection agreement were positively related. Logistic regression analysis suggested that pre-test indicators might be used to predict FRPET-GCPET concordance. CONCLUSION: In spite of methodological limitations, "first generation" GCPET devices detected sufficient FRPET positive lesions to allow prospective evaluation in clinical situations where the impact of FRPET is not confined to detection of small lesions (< 1.5 cm). The efficiency of head-to-head comparative studies would benefit from application in a clinically relevant patient spectrum, with proper blinding and standardisation of acquisition procedures.

Reproducibility and clinical value of 18F-fluorodeoxyglucose positron emission tomography in recurrent melanoma.

The purpose of this study was to assess the reproducibility and clinical impact of positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) in patients with (suspected) recurrent melanoma. The clinical value of PET was prospectively measured in 58 consecutive patients referred for PET because of unresolved clinical questions after conventional work-up. Diagnostic understanding and therapy choice by referring physicians were evaluated before, directly after, and 6 months after PET. Observer agreement of PET readings was measured with respect to various parameters (interpretation, number and localization of lesions, 'clinically decisive' metastases), using intra-class correlation coefficients. FDG PET improved diagnostic understanding in 33 cases (57%). In six patients (10%), diagnostic understanding was solely based on PET information. According to the attending clinicians, PET contributed to a positive change of planned treatment in 23 patients (40%) and increased confidence in the chosen treatment in 23 (40%). Observer agreement of PET readings was very high (intra-class correlation coefficients were between 0.87 and 0.94). The diagnostic value related especially to the whole-body scan technique and the superior specificity, compared to conventional work-up. It is concluded that, in problematical cases with (suspected) recurrent melanoma, 18F-FDG PET had considerable impact on diagnostic understanding and management. Together with the excellent observer reliability, these results justify further studies to determine the optimal place of PET in routine diagnostic algorithms in recurrent melanoma.

Systematic review of the diagnostic accuracy of (18)F-fluorodeoxyglucose positron emission tomography in melanoma patients.

BACKGROUND: Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) is a rapidly developing new imaging technique in the diagnosis and staging of melanoma. The objective of the current study was to determine the diagnostic accuracy of FDG-PET in patients with melanoma. METHODS: A systematic review and meta-analysis of clinical studies regarding FDG-PET and cutaneous melanoma was conducted. Studies were identified by a comprehensive search of the MEDLINE, EMBASE, and Current Contents databases, without any language restrictions. Eleven studies were selected. The methodologic quality of these studies was assessed independently by two reviewers. Levels of evidence and grades of recommendation were determined for each study. Six studies could be included in the statistical pooling. Sources of heterogeneity were studied by meta-regression of the diagnostic odds ratio (DOR). A summary receiver operating characteristic curve was calculated. RESULTS: The pooled sensitivity and specificity of FDG-PET in the detection of melanoma metastases were 0.79 (95% confidence interval [95% CI], 0.66-0.93) and 0.86 (95% CI, 0.78-0.95), respectively. The pooled DOR of 33.1 (95% CI, 21.9-54.0) suggests a high diagnostic accuracy for PET. Subgroup analysis revealed that PET is more accurate for systemic staging (DOR of 36.4) than for regional staging (DOR of 19.5). When used for regional staging, PET performed better in patients with American Joint Committee on Cancer Stage III disease, compared with patients with Stage I and Stage II disease. However, the methodologic quality of the studies was limited. Major problems were verification, review, and selection bias. CONCLUSIONS: Due to the poor methodologic quality of the available studies, to the authors' knowledge it is yet not possible to develop guidelines for the effective use of PET in patients with melanoma. Future accuracy studies should meet the methodologic criteria outlined in the current review.

How to perform a comprehensive search for FDG-PET literature.

In this study, a comprehensive, unbiassed search strategy for identifying literature on fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) in Medline, Embase and Current Contents was developed, with specific search strategies for each database, using MeSH terms as well as free text words for PET and FDG. To examine which text words apply to FDG, we evaluated the ways of spelling FDG in a random sample of FDG-PET articles (n = 100). These words were used as free text words in the two databases and overlap was determined. PET publications were identified using the text words "positron emission tomography" and "pet$" combined with the respective MeSH terms for each database. To compare the yield of the combined FDG-PET strategy in each database, the retrieved citations were downloaded to Pro-Cite 4.0. Finally, we added search terms for lung cancer, breast cancer, melanoma, head and neck cancer and lymphoma to our strategy and to a short strategy (consisting of the text words "positron emission tomography" and "fdg"). In order to measure the yield and precision (positive predictive value, PPV) of our search strategy and compare it with the short one, we screened the title and abstract of the retrieved citations. Reviewing a random sample of the FDG-PET literature yielded 56 different ways of spelling FDG. We confined the list to 11 text words, without missing articles. Of the publications retrieved by these text words, only 4% were indexed by the MeSH term "Fludeoxyglucose F18" in Medline and 29% by the MeSH-term "Fluorodeoxyglucose F18" in Embase. Only 51% of PET articles were indexed by the MeSH term "Tomography, emission-computed" in Medline and 40% by the MeSH term "Positron emission tomography" in Embase. The combined search strategy for identifying studies on FDG and PET resulted in 2865 publications in Medline and 2646 in Embase. Medline identified 1662 publications not found by Embase; Embase identified 1422 publications not found by Medline. Compared with the short strategy, our search strategy yielded on average 52% more publications (94%, 41% and 20% more in Medline, Embase and Current Contents, respectively). The PPV of our strategy (percent of publications that were really on PET, FDG and the specified subject) was 70%, compared with 76% using the short strategy. Regardless of the strategy used, Embase yielded more publications and was also slightly more specific than Medline. With the recommended strategy, FDG-PET publications can be identified more efficiently. We have shown the importance of searching more than one database and emphasize the use of both MeSH terms and text words in a search strategy. Standardization of the spelling of FDG and indexing of articles on FDG would substantially simplify searching.

[Follow-up after melanoma resection is more extensive than recommended in the practice guidelines, primarily for reassurance of the patient]. / Follow-up na melanoomverwijdering uitgebreider dan aanbevolen in de consensus, ter geruststelling van de patiënt.

OBJECTIVE: To determine to what extent the follow-up after resection of melanoma in practice corresponds to the relevant guidelines in the first revised version of the consensus 'Melanoma of the skin'. DESIGN: Descriptive, retrospective. METHOD: For 67 patients, who had a melanoma resected in September 1993-April 1995 in the Academic Hospital, Vrije Universiteit, Amsterdam, the Netherlands, data were collected in May-August 1997 on the first two years of follow-up from the medical records (n = 42) and through communication in writing with the referring physicians and the physicians involved in the follow-up in other hospitals in the Netherlands (n = 25). The frequency of physical examination and routine diagnostics by the doctor was evaluated. To gain insight into the reasons why in some cases the guidelines were not followed, we set up an inquiry among the 20 doctors involved in the follow-up in August 1998. RESULTS: The mean frequency of outpatient visits and physical examinations was 3-4 times per year, practically consistent with the guideline. Routine blood testing was performed in 17 patients (25%) and diagnostic imaging (X-ray or CT scan of the chest, ultrasonography of the liver) in 51 patients (76%) in deviation from the guideline. Non-compliance with the guideline could not be explained by unfamiliarity with the consensus, disagreement with the contents or existence of local protocols. Extra diagnostics were mostly meant to reassure patients. No metastases or recurrences were encountered during routine follow-up examinations, but some were found (in 8 patients) at interim visits to the outpatient clinic. CONCLUSION: The national guidelines regarding diagnostic tests in the follow-up of melanoma patients are insufficiently followed. Because redundant routine diagnostics probably have more disadvantages than benefits, a more active implementation of (future) guidelines appears necessary.

Radiopharmaceuticals in sentinel lymph-node detection - an overview.

Biopsy of the first tumour-draining lymph node (sentinel node, SN) is bound to become the procedure of choice in regional staging of melanoma and breast cancer patients. Several radiopharmaceuticals have been developed for lymphoscintigraphy. In this paper we review the most frequently used radiopharmaceuticals for their appropriateness in the sentinel-node procedure. We conclude that accurate localization of SNs is demonstrated using technetium-99m-sulfur colloid (99mTc-SC), 99mTc antimony trisulfide colloid (99mTc-ATC) [10] and 99mTc nanocolloidal albumin (99mTc-CA). 99mTc-Ca and 99mTc-SC are both available in Europe. In the United States 99mTc-SC is the only registered tracer for lymphoscintigraphy.