Objective The gene responsible for hereditary hemochromatosis close to the human leukocyte antigen A locus was previously identified and designated as HFE. This study was performed to evaluate the clinical significance of two mutations, C282Y and H63D of HFE, in Japanese patients with hepatic iron overload.
Patients and Methods We examined C282Y and H63D in 11 patients with primary hemochromatosis, 94 patients with chronic hepatitis C, 54 patients with miscellaneous liver diseases, and 151 healthy volunteers. The HFE gene region of DNA samples extracted from peripheral leukocytes was amplified by polymerase chain reaction. Restriction enzyme analysis was performed using SnaBI for C282Y and Bell for H63D. Direct sequence analysis was then performed when products suggested the presence of a mutation.
Results All the subjects studied were free from C282Y. None of the patients with hemochromatosis had H63D. One patient with chronic hepatitis C was homozygous, and 4 patients were heterozygous for H63D. Two patients with alcoholic liver disease were heterozygous for H63D. The prevalence of chromosomes with H63D was 6/188 (3.2%) in patients with chronic hepatitis C, 2/108 (1.9%) in patients with miscellaneous liver diseases, and 8/302 (2.6%) in healthy volunteers. These differences were not significant.
Conclusion Our results suggested that neither C282Y nor H63D in HFE affect Japanese patients with hemochromatosis or chronic hepatitis C.
(Internal Medicine 40: 852-856, 2001)

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Objective It is well known that bromocriptine has a suppressive effect on the prolactin release in hyperprolactinemic patients. But it also has some adverse effects. The new, long-acting dopaminergic drug, cabergoline, has been reported to be an effective agent in these patients. However, there are relatively few reports comparing the beneficial and adverse effects of these drugs in the treatment of hyperprolactinemic patients. Therefore, here we studied and compared the efficacy and tolerability of cabergoline with bromocriptine in hyperprolactinemic patients.
Patients Seventeen patients (7 with microprolactinoma, 4 with macroprolactinoma, 6 with idiopathic hyperprolactinemia) were given bromocriptine at a dose of 2.5 mg (or 5 mg for macroprolactinomas) twice daily, and 17 patients (8 with microprolactinoma, 4 with macroprolactinoma, 5 with idiopathic hyperprolactinemia) were given cabergoline at a dose of 0.5 mg twice weekly for 12 weeks.
Results At the end of the study, the prolactin reduction was significantly greater in the cabergoline group than in the bromocriptine group (-93 vs. -87.5%, respectively, p<0.05). Normalization of prolactin levels was achieved in 10 of 17 patients (59%) in the bromocriptine group, and in 14 of 17 patients (82%) in the cabergoline group (p=0.13). Two patients (50%) with macroprolactinoma in the bromocriptine group and three patients (75%) with macroprolactinoma in the cabergoline group demonstrated a normalization of their serum prolactin levels. Adverse events were noted in 53% of bromocriptine patients and in 12% of cabergoline patients (p<0.01).
Conclusion These data indicate that cabergoline is a very effective agent for lowering the prolactin levels in hyperprolactinemic patients and that it appears to offer considerable advantage over bromocriptine in terms of efficacy and tolerability.
(Internal Medicine 40: 857-861, 2001)

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Objective Recent reports have revealed that corticosteroid (PSL) therapy has a long-term beneficial effect for stabilization of renal function in progressive IgA nephropathy.
Patients and methods We analyzed serum creatinine (Cr), daily proteinuria and the results of other routine laboratory examinations during a short-term course of PSL therapy in 28 cases of progressive IgA nephropathy. The cases were divided into two groups according to changes in renal function during the PSL treatment period: group I (15 cases), improved renal function; group II (13 cases), no significant change in renal function.
Results In group I, serum Cr and proteinuria were significantly decreased, with maximum effects observed at 3 months of PSL therapy, and remained low during the period of treatment. In contrast, group II showed no significant changes in serum Cr levels during the period of therapy, although proteinuria was transiently decreased after 3 months of therapy. Histologically, cellular/fibrocellular (C/F) crescents and/or segmental glomerular necrosis (SGN) occurred with a significantly higher incidence in group I (87%) than in group II (46%) (p<0.05).
Conclusions These results suggested that the early response to PSL in reducing serum Cr and proteinuria by 3 months of treatment may be clinically useful to predict the prognosis of IgA nephropathy and that C/F crescents and/or SGN may be histologically indicative of the beneficial effects of PSL therapy in IgA nephropathy.
(Internal Medicine 40: 862-866, 2001)

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Objective In order to explore the possibility that genetic predisposition to dysfunction of mucosal immunity and the IgA processing pathway plays a role in the pathogenesis of mesangial IgAl deposition in IgAN, we examined the possible association of the gene polymorphism of pIgR in the patients with and without IgAN.
Subjects and Methods Genomic DNA of peripheral blood cells was isolated from 372 individuals including 172 histologically confirmed IgAN patients. Segments of the PIgR gene were PCR amplified and restriction fragment length polymorphism was determined as Al and A2 with and without Pvu II site, respectively.
Results The PIgR genotype distribution was significantly different between the patients with IgAN and those without IgAN. Allele frequency of A2 was higher in IgAN than in other renal diseases (Al and A2; 0.516 and 0.484 in IgAN, 0.641 and 0.359 in others, X²=9.84, P=0.0017, Odds ratio=1.71). Moreover, the subjects with A2A2 genotype were associated with a relatively low level of serum IgA only in the patients with IgAN but not in other renal diseases. The difference of allele frequencies was more remarkable in the patients with a serum IgA level of less than 300 mg/dl (Al and A2; 0.439 and 0.561 in IgAN, 0.702 and 0.298 in others, X2=12.44, P=0.0004, Odds ratio=3.01).
Conclusion This is the first demonstration of the PIgR gene polymorphisms in IgAN which are associated with its clinical phenotype. Gene polymorphisms of PIgR may be candidate genetic markers of susceptibility to IgAN.
(Internal Medicine 40: 867-872, 2001)

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Objective To evaluate the indications, efficacy, and safety of transthoracic needle aspiration (TNA) in diagnosing community-acquired pneumonia (CAP).
Methods TNA procedure was performed using an ultrathin needle with ultrasonography and/or computed tomography. The aspirate samples were Gram-stained and sent for cultures. The results were compared with those from conventional microbiological studies.
Patients Sixty patients with CAP who were admitted to the hospital and were studied prospectively between July 1994 and June 1999 were included in the study.
Results TNA culture was positive in 30 cases (50.0%). Streptococcus pneumoniae was the most frequently isolated pathogen, followed by the Streptococcus milleri group, and anaerobes. The results of TNA were consistent with those of quantitative sputum cultures in 9 patients and with those of blood cultures in 4. Complications arose in 3 patients who developed small to moderate pneumothorax.
Conclusions TNA is a safe procedure with a good diagnostic yield. In particular, anaerobes or microaerophils such as the S. milleri group were highly detectable by TNA. The results obtained by TNA were highly consistent with those obtained by the gold standard methods. Combined with conventional methods, TNA is considered highly useful for determining the etiology of CAP.
(Internal Medicine 40: 873-877, 2001)

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_Objective B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) has been increasingly reported in Asia and is regarded as a variant of intravascular lymphomatosis (IVL). Recently CDS was reported to be expressed in some cases of diffuse large cell lymphoma and IVL. We therefore examined the expression of CDS on lymphoma cells in B-LAHS and compared the clinical and laboratory data between CD5+ and CD5- B-LAHS.
Methods The expression of CDS on lymphoma cells was examined using flow cytometry and immunohistochemical analysis of paraffin sections. The clinical records were reviewed to characterize clinical features.
Patients Twelve patients with B-LAHS; ten men and two women, age ranging from 41 to 82 years (median, 63.5 years) were included in this study.
Results B-LAHS is characterized by fever and hepatosplenomegaly without lymphadenopathy at the initial presentation. Histological examination showed hemophagocytosis and infiltration of lymphoma cells in the bone marrow, and in some cases intravascular proliferation of lymphoid cells characteristic of IVL. All patients showed increased levels of lactate dehydrogenase, C-reactive protein, ferritin and soluble interleukin-2 receptor. In eight of the twelve patients, lymphoma cells were positive for CDS. But no differences were observed in the clinical or laboratory findings between CD5+ B-LAHS and CDS- B-LAHS.
Conclusion No clinical differences were observed between CDS* B-LAHS and CDS- B-LAHS. Further studies are required to elucidate the differences in pathogenesis between these two subgroups of B-LAHS.
(Internal Medicine 40: 878-882, 2001)

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We report a patient with ulcerative colitis complicated with idiopatic interstitial pneumonia, in whom the etiology of interstitial pneumonia was unknown, but immunological disturbance might have been involved. There are many complications with ulcerative colitis, but interstitial pneumonia is quite rare and its prognosis is quite poor. Antibiotic and steroid treatment were given under respiration supported therapy, but no response could be obtained. In the treatment of patients with ulcerative colitis, we must be mindful of interstitial pneumonia because the prognosis is quite poor.
(Internal Medicine 40: 883-886, 2001)

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We report here a case of an unusual extrahepatic portosystemic venous shunt in a 37-year-old woman without liver cirrhosis or portal hypertension, who developed portal systemic encephalopathy. Angiography demonstrated an inferior mesenteric-caval shunt characterized by the presence of direct communication of the inferior mesenteric vein with the left internal iliac vein. After the treatment with percutaneous transcatheter embolization of the shunt via a femoral vein approach using coils, she had no episode of portal systemic encephalopathy.
(Internal Medicine 40: 887-890, 2001)

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A 23-year-old woman was admitted to our hospital with recurrent gouty arthritis. Laboratory findings showed hypoglycemia, lactic acidosis, hyperlipidemia, and hyperuricemia, with normal values of serum alfa-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKA-II). A diagnosis of glycogen storage disease type I (GSD-type I) was made on the basis of the laboratory data, liver biopsy findings, and partially deficient thrombocyte glucose-6-phosphatase (G-6-Pase) activity. Ultrasonography and computed tomography revealed multiple focal hepatic masses. Biopsied specimens of the lesion demonstrated a hepatic adenoma, which changed in appearance in the relatively short period between echography and computed tomography. This interesting phenomenon may highlight the importance for careful follow-up of hepatic adenomas, because of the potential of rupture, hemorrhage, or malignant transformation. During follow-up, the present patient received hemodialysis due to renal failure, and the adenoma regressed spontaneously after 8 years. Included are diagnostic images, demonstrating the association of hepatic adenoma and GSD-type I.
(Internal Medicine 40: 891-895, 2001)

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A 67-year-old woman was admitted to our hospital with a complaint of abdominal pain. Barium enema examination and colonoscopy showed numerous round polypoid lesions covered with normal mucosa in the area from the ascending colon to the splenic flexure. Endoscopic ultrasound examination with an ultrasonic catheter probe revealed a strong echo with distal acoustic shadowing in the third layer of the diseased colonic wall, which suggested the presence of gas in the submucosa. The gaseous cysts disappeared completely after hyberbaric oxygen therapy at 2 to 3 atmospheres absolute (60 minutes, twice a day) for 30 consecutive days.
(Internal Medicine 40: 896-900, 2001)

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A 17-year-old male who had been diagnosed with ulcerative colitis was prescribed 80 mg prednisolone and 1, 500 nig 5-aminosalicylic acid (5-ASA) per day. Two weeks after initiating therapy, he was referred to our hospital for evaluation of chest pain and high fever. Electrocardiography (ECG) showed ST elevation in limb and precordial leads. Chest pain with high fever and ECG changes were resolved after 5-ASA was discontinued. Three weeks later, the administration of a low dose of 5-ASA was associated with the immediate recurrence of pericarditis associated with chest pain, suggesting a hypersensitive reaction to 5-ASA in this patient.
(Internal Medicine 40: 901-904, 2001)

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A 32-year-old Japanese man was hospitalized for evaluation of unconsciousness. He was diagnosed as having primary pulmonary hypertension (PPH) with severe systemic hypertension, Raynaud's phenomenon and relative polycythemia. Hemostatic studies revealed increased coagulation and decreased fibrinolysis, similar to findings of chronic disseminated intravascular coagulation (DIG). Although activation of coagulation and systemic hypertension were improved after treatment with phlebotomy and administration of nifedipine, enerapril and warfarin, pulmonary hypertension was unchanged, suggesting that irreversible change had already occurred in the pulmonary arteries. Those complications could modify the process of pulmonary hypertension by inducing a hyperviscosity state.
(Internal Medicine 40: 905-910, 2001)

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A 71-year-old woman showed disorientation 7 days after simple mastectomy for right breast cancer. Computed tomography of the brain was normal. The level of serum sodium was very low (110 mEq/l), while the urine sodium level was normal. The osmolality of urine was higher (342 mosmol/kg) than that of serum (220 mosmol/kg). These data suggested a syndrome of inappropriate secretion of anticliuretic hormone. A fluid restriction, infusion of hypertonic saline and administration of diuretics gradually increased the level of serum sodium. Subsequently, disorientation disappeared. This is a rare case of the syndrome of inappropriate secretion of antidiuretic hormone caused by simple mastectomy, a relatively minor surgical procedure.
(Internal Medicine 40: 911-914, 2001)

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A 38-year-old man presented with headache, fever, and double vision associated with right abducens nerve paresis. He had neither nuchal rigidity nor visual field defect. Laboratory data revealed elevated erythrocyte sedimentation rate (ESR), eosinophilia, and lymphocytic pleocytosis in the cerebrospinal fluid (CSF). Provocation tests of pituitary hormones showed partial hypopituitarism. Magnetic resonance imaging (MRI) revealed swelling of the hypophysis and a mass lesion expanding into the right cavernous sinus. The supplement dose of dexamethasone for hypothalamic hypocortisolism manifested diabetes insipidus. Biopsy, carried out through the transsphenoidal approach, revealed giant cell granuloma. Systemic granulomatous diseases were ruled out, and the lesion was considered to be idiopathic giant cell granulomatous hypophysitis. Right abducens nerve paresis, diabetes insipidus and dysfunction of the anterior lobe were amended by the treatment with prednisolone for 4 months, and findings of the pituitary gland and stalk were normalized. The present case shows that glucocorticoid has an effect on amendment of idiopathic giant cell granulomatous hypophysitis.
(Internal Medicine 40: 915-919, 2001)

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A 45-year-old woman was admitted because of hypertension and hypokalemia. Primary amenorrhea from birth was noted. Plasma renin activity (PRA), 17α-hydroxyprogesterone and androgen levels were low, but progesterone, 11-deoxycorticosterone, corticosterone and adrenocorticotropic hormone (ACTH) were elevated, resulting in a diagnosis of 17α-hydroxylase deficiency. Abdominal magnetic resonance imaging revealed a round mass in the left adrenal region, the specimen of which was diagnosed as myelolipoma. After removal of the tumor, the blood pressure, serum potassium and hormone levels were unchanged, indicating an adrenal non-functioning tumor. Excessive ACTH secretion over a long period may stimulate the development of adrenal myelolipoma.
(Internal Medicine 40: 920-923, 2001)

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A 59-year-old man who had received chronic hemodialysis developed left occipital pain and hypoglossal nerve palsy. He was diagnosed as having skull base metastasis from renal cell carcinoma related to acquired cystic kidney. Retrospective analysis revealed the patient had had elevated serum C-reactive protein and alkaline phosphatase levels before the symptoms appeared. Radiotherapy to the skull base relieved the pain. Finally he died with generalized metastases. Serum interleukin-6 levels measured during admission had been elevated, and interleukin-6 mRNA was detected in the autopsy specimen of renal cell carcinoma. Interleukin-6 might be involved in the etiology of paraneoplastic signs.
(Internal Medicine 40: 924-930, 2001)

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A 45-year-old male was admitted because of chest pain, lumbago, and bilateral ankle pain. Examination disclosed hypophosphatemic osteomalacia, acquired Fanconi syndrome, and abnormalities in distal nephron such as distal renal tubular acidosis and renal diabetes insipidus. Further exploration revealed IgA kappa multiple myeloma excreting urinary Bence Jones protein (kappa-light chain). Renal biopsy revealed thick basement membranes and electron-dense crystals in proximal tubular epithelial cells. Immunofluorescent studies revealed deposition of kappalight chain in renal tubular epithelial cells that caused the renal tubular damage. Although the osteomalacia was relieved by medical treatment, the urinary Bence Jones protein and the renal tubular defects were not improved by the chemotherapy for the myeloma. The patient died of exacerbation of multiple myeloma at 50 years of age.
(Internal Medicine 40: 931-935, 2001)

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A case of systemic rhabomyolysis after acetonitrile exposure is reported. A 35-year-old previously healthy man suffered from vomiting, convulsion and consciousness loss 15 hours after exposure to acetonitrile. Since acetonitrile is known to be metabolized into cyanide, antidote therapy against cyanide poisoning was given. On admission, pain and all-over muscle swelling were marked. Although the initial therapy was effective, rhabdomyolysis and then acute renal failure developed. Renal function improved very slowly after six weeks of hemodialysis, but atrophy of the muscles remained. The rhabdomyolysis may have been caused by toxicity of the cyanide itself in combination with hypoxia and convulsion.
(Internal Medicine 40: 936-939, 2001)

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We report a patient with a severe inclusion body myositis (IBM). His illness was unusual in terms of a rapid progression, high creatine kinase levels, and complication with interstitial pneumonia. He responded well to immunosuppressive agents such as corticosteroids, cyclosporin A, cyclophosphamide, and immunoglobulin. The present patient indicates the wide range of the disease, and that immunosuppressive agents may be useful for treatment of IBM.
(Internal Medicine 40: 940-944, 2001)

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We describe a 27-year-old woman with disseminated intravascular coagulation and shock due to amniotic fluid embolism after Caesarean section who responded well to continuous hemodiafiltration (CHDF) therapy. The effectiveness of CHDF in treating amniotic fluid embolism is also discussed.
(Internal Medicine 40: 945-947, 2001)

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A case of neurofibromatosis type 1 (NF1) manifesting Wallenberg's syndrome and fusiform aneurysm of the basilar artery is reported. The patient suddenly developed dysarthria, walking difficulty and sensory disturbance. Neurological examination suggested Wallenberg's syndrome and MR imaging confirmed an ischemic lesion at the left lateral medulla oblongata. Cerebral angiography revealed a fusiform aneurysm at the middle portion of the basilar artery. However, there was no occlusive change in either the posterior inferior cerebellar artery or the vertebral artery. The clinical and radiological features are discussed together with a review of NF1 cases with intracranial aneurysms in the literature.
(Internal Medicine 40: 948-951, 2001)

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The plasma of a patient with myasthenia gravis had strong lupus anticoagulant activity and his IgM paraprotein displayed non-specific inhibition to coagulation factors IX, XI, XII, prekallikrein, and high molecular weight kininogen. He was placed on prednisolone, which resulted in improvement in his myasthenic symptoms, but the prolongation of APTT and macroglobulinemia remained. Double filtration plasmapheresis successfully decreased the serum IgM level from 1, 190 mg/dl to 375 mg/dl and APTT improved from 58 s to 38 s. Myasthenia gravis is frequently associated with other autoimmune diseases, but the association with lupus anticoagulant and IgM gammopathy is rare.
(Internal Medicine 40: 952-955, 2001)

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Since malignant melanoma is a rare malignancy in Japan, little is known about the cytogenetic abnormalities in Japanese patients. We report a case of malignant melanoma showing complex chromosomal abnormalities. A 70-yearold woman was admitted to our hospital because of anorexia, delirium, and right hemiplegia. Cranial CT disclosed several metastatic brain tumors. Multiple subcutaneous and intra-abdominal metastases were also found. A diagnosis of metastatic malignant melanoma was made by biopsy of a subcutaneous tumor. Chromosomal analysis of the tumor cells disclosed complex karyotypic abnormalities including novel unbalanced whole arm translocations der (8; 14) (q10; q10) and der (11; 15) (q10; q10).
(Internal Medicine 40: 956-960, 2001)

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A previously healthy 60-year-old man had a two-year history of dizziness or faintness when eating but not when drinking. MRI of the brain detected deep venous dilatation, and digital subtraction cerebral angiography showed superior sagittal sinus thrombosis. These symptoms were completely resolved after the daily administration of 200 mg ticlopidine for four weeks. The pathomechanism of this unusual presentation is speculated episodic congestion of the jugular venous drainage during mealtime due to an increase in the circulatory volume of the external carotidjugular system.
(Internal Medicine 40: 961-963, 2001)

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This is the first report of a patient presenting with rheumatoid factor (RF) positive hypertrophic cranial pachymeningitis (HCP) in association with hypopituitarisni and multiple cranial nerve palsies. Our patient developed palsies of the left II and III, bilateral VI and VII, and right IX, X, and XII cranial nerves. A stimulation test showed hypopituitarism due to hypothalamic failure. The patient was seropositive for RF but had no multiple joint pain or deformities. Magnetic resonance imaging (MRI) showed thickened dura of the sellar and parasellar region, hypothalamus, bilateral cavernous sinuses and the tentorium all of which were enhanced by gadolinium (Gd). Treatment with prednisone improved clinical symptoms and MRI findings concomitant with reduction of RF titer. Although the exact mechanism of HCP has not been clearly elucidated, the present case suggests an autoimmune mechanism associated with RF.
(Internal Medicine 40: 964-967, 2001)

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Glutamic acid decarboxylase (GAD) is the main target of humoral autoimmunity in patients with insulin-dependent diabetes mellitus (IDDM) and stiff-person syndrome. We reviewed the case of a 46-year-old woman who had cerebellar ataxia before getting stiff-person syndrome and IDDM with high anti-GAD autoantibody titers. This was a rare case in which there were both the clinical symptoms of stiff-person syndrome and cerebellar ataxia. In western blot analysis her serum reacted with 65-kDa proteins from rat cerebellum, cerebral cortex, and spinal cord. Autoantibodies to GAD may cause functional impairment of γ-aminobutyric acid (GABA) neurons in the spinal cord as well as in the cerebellum.
(Internal Medicine 40: 968-971, 2001)

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Tabes dorsalis is uncommon and progresses slowly from infection to clinical manifestation. We report a rare case of rapidly progressive tabes dorsalis associated with selective IgA deficiency (slgAD). A 28-year-old man was hospitalized with lightning back pain, nausea, and bladder bowel dysfunction. Serum and cerebrospinal fluid (CSF) revealed high liters of Treponema pallidum antibody, and the serum IgA level was less than 5 mg/dl. Thl-dominant cytokine expression was observed, as is usually seen in neurosyphilis. He was treated with Ceftriaxone and CSF pleocytosis disappeared. We postulate slgAD influenced the atypical rapid clinical course of tabes dorsalis in this patient.
(Internal Medicine 40: 972-975, 2001)

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