Serological testing for anti-neutrophil cytoplasmic antibodies (ANCA) has become an important tool for supporting a diagnosis of systemic necrotizing small vessel vasculitis: Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and oligo-symptomatic forms of these. These so-called ANCA-associated vasculitides most often necessitate the institution of therapies with cytotoxic as well as anti-inflammatory agents, and hence, a firmly established diagnosis is mandatory to avoid unnecessary and risky treatment. In the laboratory of today the most appropriate way to detect the presence of vasculitis-associated ANCA is by using both indirect immunofluorescence and direct enzyme immuno-assay for antibodies to proteinase 3 and myeloperoxidase. The diagnostic specificity of these latter assays towards systemic vasculitis can only be secured by setting a suitably high cut-off value, chosen in collaboration with clinicians after testing carefully selected disease control sera. When classical cytoplasmic ANCA as well as a significant level of proteinase 3-ANCA are found in a given serum this combined result strongly indicates vasculitis. Similarly, the combination of perinuclear ANCA and a significant level of myeloperoxidase-ANCA is close to 100% specific for vasculitis.
(Internal Medicine 40: 466-470, 2001)

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Objective After the initial clinical application of peripheral blood stem cell transplantation (PBSCT) in the latter half of the 1980s, the frequency of PBSCT for non-Hodgkin's lymphoma (NHL) has been gradually increasing. At present, PBSCT is an important procedure for treating young patients with NHL. This procedure is now being increasingly used as a part of the chemotherapy regimen for elderly patients. We evaluated the feasibility of PBSCT in elderly patients with malignant lymphoma.
Patients and Methods We performed PBSCT on four older patients over 65 years old (median age 71, range 66-78) with aggressive non-Hodgkin's lymphoma. Patients were initially treated with the THP-COP [cyclophosphamide, THP-doxorubicin (pirarubicin), vincristine, prednisolone] regimen as first-line chemotherapy. As second-line chemotherapy, in partial response (PR) cases, we performed PBSCT. Conditioning therapy was the MCVC [ranimustine (MCNU), carboplatin, etoposide (VP-16), cyclophosphamide] protocol.
Results PBSC collection and transplantation were possible in all patients. We observed no severe toxicity. Two of the four patients attained complete remission (CR). Tumor size was clearly diminished in two PR patients. Performance status (PS) was improved in three of the four patients after transplantation.
Conclusion Despite the small number of cases, this procedure is beneficial for completing chemotherapy earlier and promoting a good quality of life.
(Internal Medicine 40: 471-474, 2001)

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Objective We analyzed the usefulness of transesophageal echocardiography (TEE) for detection of cardiac diseases in patients with retinal artery occlusion (RAO).
Patients and Methods We retrospectively reviewed the charts of 22 consecutive patients with acute RAO. The patients had been evaluated by conventional studies, including transthoracic echocardiography (TTE) and TEE.
Results TEE findings were abnormal in 13 (59 %) of the 22 patients. The findings revealed a decrease of flow velocity in the left atrial appendage (n=7), atrial septal aneurysm (n=4), patent foramen ovale (n=2), spontaneous echo contrast (n=l), ascending aortic plaque (n=l) and left atrial thrombus (n=l). Evaluations, including TEE, disclosed cardiac abnormalities in 16 (73%) of these 22 patients. However, excluding the analysis by TEE, cardiac abnormalities were revealed in only 6 (27%) patients.
Conclusion In patients with RAO, TEE may be a useful examination for detecting potential cardiac diseases.
(Internal Medicine 40: 475-478, 2001)

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Most patients with hereditary hemochromatosis are homozygous for C282Y in the HFE gene in populations of Celtic origin, but the genetic cause of this disease is unknown in Japan because of its rarity. A 48-year-old Japanese patient was recently diagnosed with idiopathic hemochromatosis. Analysis of the entire coding region of the patient's HFE by RT-PCR showed a heterozygous nucleotide substitution at nucleotide 527 from C to T, which resulted in A176V amino acid substitution. Another mutation at nucleotide 942 from T to C was observed, but this was a nonsense mutation. C282Y and another mutation, H63D, were not found in the patient. The mutation may have a possible role on the cause of hemochromatosis in this Japanese case.
(Internal Medicine 40: 479-483, 2001)

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A 76-year-old woman admitted to our hospital for jaundice had been treated for diabetes mellitus with insulin for 9 years and voglibose had been added for the 39 months preceding admission. Elevated serum bilirubin and transaminase concentration began to normalize with initiation of corticosteroid treatment 1 week after discontinuation of voglibose. In the in vitro testing of the patient's peripheral blood, lymphocytes showed stimulation by voglibose. In dramatic contrast to an initial liver biopsy specimen that demonstrated cholestasis with submassive and zonal necrosis, the follow-up specimen was normal 1 year later. We believe that patients treated with voglibose should be monitored long-term with monthly determinations of transaminases and bilirubin in serum.
(Internal Medicine 40: 484-188, 2001)

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A 44-year-old man with chronic hepatitis C received three courses of interferon (IFN) therapy. HCV genotype was 1b, viral load was 1, 200 kcopies/ml and interferon sensitivity determining region (ISDR) was the intermediate type before the 1st IFN therapy. The 1st and 2nd IFN therapies resulted in failure to yield a sustained response. Seven years after from the 1st therapy, viral load had decreased to 15 kcopies/ml and ISDR had changed to mutant type. The 3rd IFN therapy yielded sustained response. Thus, we should consider retreatment with IFN when a decrease of the viral load and change of ISDR to mutant type are observed.
(Internal Medicine 40: 489-492, 2001)

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Inflammatory pseudotumor (IPT) of the liver is a rare benign lesion of unknown etiology and is often accompanied by fever. Unexplained persistent fever unresponsive to antibiotics developed in a 70-year-old man suffering from intractable recurrent gouty arthritis. ⁶⁷Ga-scintigraphy disclosed intense focal uptake in the upper abdomen. The lesion in the left lobe of the liver was an ill-defined hypodensity mass on computed tomographic scan and was enhanced on dynamic magnetic resonance imaging. The tumor was surgically removed and a diagnosis of IPT was made. Fever and arthritis resolved completely after surgery. Possible interaction between IPT of the liver and gouty arthritis was suggested.
(Internal Medicine 40: 493-498, 2001)

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Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder characterized by tumors of the enteropancreas, parathyroid and anterior pituitary. The MEN 1 gene was recently cloned, and germline mutations of the gene have been demonstrated in cases of MEN 1. Here, we report a Japanese family with a germline mutation of the MEN 1 gene. The proband (44 y.o., male) had primary hyperparathyroidism (PHP) and pancreatic carcinoid, and his older sister (50 y.o.) had a history of parathyroidectomy for primary hyperparathyrodism at the age of 40. Clinical examination revealed no evidence of PHP or other MEN 1-related tumors in his son. Direct sequencing analysis revealed a heterozygous germline mutation (1001delC) at codon 297 in exon 6 of the MEN 1 gene in the proband and his son. Loss of heterozygosity (LOH) was also found in the resected parathyroid tissue of the proband. The deletion of cytosine 1001 observed in this case induces a frame shift, which causes the appearance of a stop codon (TAG) at codon 367. This mutation appears to be associated with tumors of the endocrine tissues in the cases studied.
(Internal Medicine 40: 499-505, 2001)

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We herewith report an unusual case of primary hyperparathyroidism whose parathyroid adenoma strongly accumulated technetium (Tc)-99m pertechnetate. A 41-yearold woman was referred to our department under the tentative diagnosis of primary hyperparathyroidism. Scintigraphy by thallium-201 chloride showed homogeneous uptake in the whole thyroid, whereas Tc-99m image revealed a strong local accumulation in the middle portion of the right thyroidal lobe. Neck exploration revealed a 12×8×5-mm tumor in the posterolateral region of the right thyroidal lobe, the pathology of which was parathyroid adenoma. In addition, a small nodule (8 mm in diameter) with pathological findings revealing follicular adenoma of the thyroid, was found within the medial portion of the right thyroidal lobe. Both lesions were removed by surgery, and a postoperative Tc-99m scintigraphy no longer demonstrated a significant uptake in the right thyroidal lobe. Since the thyroid adenoma was too small to be detected by any scintigraphic study and located much closer to the median line than the site of the marked accumulation of Tc-99m pertechnetate, it was considered very likely that the parathyroid adenoma concentrated Tc-99m. Search of literature revealed that there have been only thirteen cases of parathyroid tumor reported to date which significantly accumulated Tc-99m pertechnetate. The present patient represents another rare case of parathyroid adenoma showing such an unusual scintigraphic image.
(Internal Medicine 40: 506-509, 2001)

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We report 3 patients with isolated adrenocorticotropin (ACTH) deficiency presenting with neuroleptic malignant syndrome (NMS)-like symptoms. All patients were in their 60's or 70's and showed consciousness disturbance, a high-grade fever, extrapyramydal signs, and muscle enzyme elevations, which met the criteria for NMS. Also, they all showed hyponatremia induced by isolated ACTH deficiency. In addition to the standard therapy for NMS, corticosteroid supplement therapy was effective in all patients. There thus appear to be subjects with isolated ACTH deficiency among patients presenting with NMS-like symptoms, and adrenal and pituitary function should be checked in NMS patients with hyponatremia.
(Internal Medicine 40: 510-514, 2001)

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A 24-year-old female suffered from acute pancreatitis, followed by simultaneous onset of painless goiter, elevation of thyroid hormones and diabetic ketoacidosis. Two months later, her insulin secreting function was severely decreased and positive for anti-GAD and anti-islet cell antibodies, whereas the serum glucagon level was normal, suggesting an autoimmune-related destruction specifically of β cells. In addition, the initial hyperthyroid state was followed by a hypothyroid phase which later recovered to an euthyroid state, suggesting an initial destruction of thyroid cells. Because anti-thyroidal antibodies were positive, it is likely that the thyroidal destruction was also autoimmune-related. This case implies common pathogenic mechanisms in the autoinimunity related destruction of β cells and thyroid cells.
(Internal Medicine 40: 515-518, 2001)

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Glycosuria was detected in a 37-year-old Chinese woman by a urinary examination in a local clinic with clinical evidence of acute pyelonephritis (APN). Transient glycosuria is an unusual complication of acute pyelonephritis in nondiabetic patients. As there is growing prevalence of type 2 diabetes in the population worldwide, it must be recognized that mistaken diagnosis of diabetes mellitus by glycosuria may predispose patients to an unfavorable hypoglycemic episode. Thus definite diagnosis of diabetes mellitus should be made only after recovery of APN by means of urinalysis or by simultaneous blood glucose concentration analysis.
(Internal Medicine 40: 519-521, 2001)

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There is increasing appreciation for the presence of diseases which do not fit the criteria for classic cystic fibrosis but are caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR). This case describes a patient with documented CFTR dysfunction by nasal potential difference measurement who presents with chronic idiopathic pancreatitis, sinusitis, and allergic bronchopulmonary aspergillosis (ABPA), but not congenital bilateral absence of the vas deferens (CBAVD) or other classic symptoms of cystic fibrosis. This rare case demonstrates both the spectrum of disease which can be seen with CFTR dysfunction and the steps required to document CFTR involvement.
(Internal Medicine 40: 522-525, 2001)

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A 41-year-old man fell into type II respiratory failure after catching a cold, and became dependent on a respirator. Chest radiography showed no abnormalities and the hyperventilation test showed improved arterial blood gas findings. His sleep study showed marked nocturnal desaturation due to hypopnea and apnea with a decrease of thoracic and abdominal movement during sleep. Therefore, we diagnosed him as primary alveolar hypoventilation syndrome (PAH). Seven years previously, his 2-year elder sister had suffered from similar respiratory failure during her second pregnancy and had been diagnosed as PAH. While myopathy was suspected in both cases, attenuation of muscle strength was slight and it appeared not to be the main cause of alveolar hypoventilation. Since medication was not effective in each case, they underwent non-invasive positive pressure ventilation (NIPPV). While sustained mild hypercapnia remained during the daytime, it improved their respiratory failure. To our knowledge, this is the first study of familial adult onset PAH.
(Internal Medicine 40: 526-531, 2001)

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Hypertrophic pulmonary osteoarthropathy (HPO) associated with non-small cell lung cancer in a 58-year-old man was accompanied by an elevated serum level of growth hormone (GH). HPO rapidly disappeared after resection of the primary tumor and the elevation of serum GH was resolved. Immunohistochemically the tumor contained growth hormone-releasing hormone (GHRH) but not GH. These findings suggest that the high serum GH level due to ectopic GHRH production in the tumor, was a contributing factor in HPO. This is the second reported case of non-small cell lung cancer which was immunohistochemically positive for GHRH associated with HPO.
(Internal Medicine 40: 532-535, 2001)

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We treated a rare case of malignant fibrous histiocytoma (MFH) of soft tissue that produced granulocyte colonystimulating factor (G-CSF). The patient, an 80-year-old woman, was admitted because of a feeling of abdominal fullness and leg edema. An elastic, hard, tender tumor was palpated in the right thigh. Histopathological examinations of the tumor revealed atypical and prominent pleomorphic spindle-shaped cells with funicular arrangement, which were compatible with the diagnosis of MFH. Prominent leukocytosis (up to 84, 300/μl), a high serum G-CSF concentration (82 pg/ml) and positive immunohistochemical staining of the tumor tissue for G-CSF indicated that G-CSF was produced by the MFH.
(Internal Medicine 40: 536-540, 2001)

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A patient with systemic lupus erythematosus (SLE) developed acquired hemophilia A. The patient, a 24-year-old Japanese woman, was referred to our hospital because of uncontrollable bleeding following a tooth extraction. Laboratory examination revealed prolonged APTT (116 seconds), reduced factor VIII activity (2.8%) and the presence of factor VIII inhibitor at a titer of 46.5 Bethesda units/ml. Transfusion of prothrombin complex concentrate and activated prothrombin complex concentrate followed by administration of prednisolone and cyclophosphamide successfully arrested bleeding and reduced the factor VIII inhibitor level. Acquired hemophilia A is a rare but lethal condition. Rapid diagnosis and introduction of adequate therapies are critical.
(Internal Medicine 40: 541-543, 2001)

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A woman with a long history of chronic bronchitis and chronic sinusitis, i.e., sinobronchial syndrome, was admitted with a fever. Radiologically, there were areas of longstanding consolidation in both lungs, with areas of active inflammation demonstrated by gaIlium-67 scintigraphy. Antineutrophil cytoplasmic antibody specific for myeloperoxidase was highly positive. Pulmonary hemorrhage and hematuria occurred 2 weeks after admission and responded to steroid therapy. However, the patient died of pneumonia. An autopsy revealed systemic necrotizing vasculitis affecting multiple organs, consistent with microscopic polyangiitis. The vasculitis might have been caused by the chronic inflammation in the lungs associated with sinobronchial syndrome.
(Internal Medicine 40: 544-547, 2001)

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