Acromegaly caused by growth hormone-releasing hormone-producing tumors: long-term observational studies in three patients

We report on three newly diagnosed patients with extracranial ectopic GHRH-associated acromegaly with long-term follow-up after surgery of the primary tumor. One patient with a pancreatic tumor and two parathyroid adenomas was the index case of a large kindred of MEN-I syndrome. The other two patients had a large bronchial carcinoid. The first patient is still in remission now almost 22 years after surgery. In the two other patients GHRH did not normalize completely after surgery and they are now treated with slow-release octreotide. IGF-I normalized in all patients. During medical treatment basal GH secretion remained (slightly) elevated and secretory regularity was decreased in 24 h blood sampling studies. We did not observe development of tachyphylaxis towards the drug or radiological evidence of (growing) metastases. We propose life-long suppressive therapy with somatostatin analogs in cases with persisting elevated serum GHRH concentrations after removal of the primary tumor. Independent parameters of residual disease are elevated basal (nonpulsatile) GH secretion and decreased GH secretory regularity.     

Neuroendocrine tumors secreting growth hormone-releasing hormone: Pathophysiological and clinical aspects

Hypothalamic GHRH is secreted into the portal system, binds to specific surface receptors of the somatotroph cell and elicits intracellular signals that modulate pituitary GH synthesis and/or secretion. Moreover, GHRH is synthesized and expressed in multiple extrapituitary tissues. Excessive peripheral production of GHRH by a tumor source would therefore be expected to cause somatotroph cell hyperstimulation, increased GH secretion and eventually pituitary acromegaly. Immunoreactive GHRH is present in several tumors, including carcinoid tumors, pancreatic cell tumors, small cell lung cancers, endometrial tumors, adrenal adenomas, and pheochromocytomas which have been reported to secrete GHRH. Acromegaly in these patients, however, is uncommon. The distinction of pituitary vs. extrapituitary acromegaly is extremely important in planning effective management. Regardless of the cause, GH and IGF-1 are invariably elevated and GH levels fail to suppress (<1 μg/l) after an oral glucose load in all forms of acromegaly. Dynamic pituitary tests are not helpful in distinguishing acromegalic patients with pituitary tumors from those harbouring extrapituitary tumors. Plasma GHRH levels are usually elevated in patients with peripheral GHRH-secreting tumors, and are normal or low in patients with pituitary acromegaly. Unique and unexpected clinical features in an acromegalic patient, including respiratory wheezing or dyspnea, facial flushing, peptic ulcers, or renal stones sometimes are helpful in alerting the physician to diagnosing non pituitary endocrine tumors. If no facility to measure plasma GHRH is available, and in the absence of MRI evidence of pituitary adenoma, a CT scan of the thorax and abdominal ultrasound could be performed to exclude with good approximation the possibility of an ectopic GHRH syndrome. Surgical resection of the tumor secreting ectopic GHRH should be the logical approach to a patient with ectopic GHRH syndrome. Standard chemotherapy directed at GHRH-producing carcinoid tumors is generally unsuccessful in controlling the activated GH axis. Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, long-acting somatostatin analogs may be able to control not only the ectopic hormonal secretion syndrome, but also, in some instances, tumor growth. Therefore, although cytotoxic chemotherapy, pituitary surgery, or irradiation still remain available therapeutic options, long-acting somatostatin analogs are now preferred as a second-line therapy in patients with carcinoid tumors and ectopic GHRH-syndrome.     

Growth hormone-producing pituitary adenomas in childhood and young adulthood: clinical features and outcomes

Purpose

Growth hormone (GH)-producing pituitary adenomas (PAs) in childhood or young adulthood are rare, and the details surrounding these tumors remain enigmatic. We present the clinical, pathological and genetic features of this disease.

Methods

We identified 25 patients aged 20 years or younger with GH-producing PAs who underwent surgery between 2003 and 2016 at Toranomon Hospital in Tokyo. We retrospectively reviewed the clinical data, treatment outcomes and pathological features of these patients to shed light on childhood acromegaly.

Results

The cohort comprised 14 male and 11 female patients whose average age at the time of surgery was 17.3 years. Germline AIP mutations were present in 5 of 13 patients examined, and Carney complex was identified in 2 of 25 patients. The mean maximum tumor diameter was 26.7 mm, and total resection assessed during surgery was achieved in 17 patients. Based on their respective pathological findings, patients were divided into the following 4 groups: sparsely granulated adenomas (5), densely granulated (DG) adenomas (6), plurihormonal adenomas (9), and silent subtype 3 (SS3) adenomas (5). During the mean follow-up period of 50.3 months, complete endocrinological remission was achieved in 14 of 25 patients (56%) by surgery alone and in 19 patients (76%) after postoperative adjuvant therapy.

Conclusions

GH-producing PAs in young patients are intriguing and difficult to treat due to their distinct tumor characteristics, including a lower incidence of the DG subtype and a higher incidence of SS3 adenomas and genetic abnormalities. Therefore, multi-modal therapies are essential to achieve optimal clinical outcomes.

     

Steroid hormone-producing tumors of the adrenal, ovary, and testes.

Steroid hormone-synthesizing tumors are rare and may be difficult to diagnose and treat. This article focuses on adrenal tumors as models for the even less common tumors of the ovary and testes, and emphasizes useful diagnostic procedures and pitfalls as well as treatment options. Ovarian and testicular steroidogenic tumors are categorized and discussed in terms of the generalizations that can be derived from adrenal neoplasia.     

The liver in consecutive patients with morbid obesity: a clinical, morphological, and biochemical study

Liver morphology and biochemistry were investigated in 61 morbidly obese subjects selected by defined criteria. Median overweight was 82 per cent (range 61 to 170 per cent), and median duration of overweight was 20 years (range two to 45 years). No patient had more than a moderate alcohol consumption and only one was diabetic. Four biopsies (7 per cent) showed normal liver tissue, while fatty change was the main diagnosis in most cases (85 per cent). Increasing degrees of fatty change was significantly (P less than 0.02) associated with presence of lipogranulomas (found in 54 per cent of the biopsies), focal necroses (found in 28 per cent), slight parenchymal inflammation (found in 33 per cent), and Kupffer cell proliferation (found in 49 per cent). Slight portal inflammation was seen in 23 per cent but portal fibrosis in only 2 per cent of the biopsies. No case of cirrhosis was registered. Patients with moderate or severe fatty change, lipogranulomas , focal necroses or with parenchymal inflammation were significantly more obese than patients without these changes (P less than 0.05). Even in absence of fatty change, obese subjects showed a markedly decreased serum albumin concentration and an elevated serum alkaline phosphatase activity (P less than 0.0001) compared with non-obese controls. Serum lactate dehydrogenase and aspartate aminotransferase were significantly raised only in patients with fatty change. With respect to serum bilirubin and plasma cholesterol concentrations no significant differences were detected between patient subgroups and controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Verapamil ameliorates clinical, pathologic and biochemical manifestations of experimental chagasic cardiomyopathy in mice

The influence of long-term verapamil administration on the consequences of Trypanosoma cruzi infection in mice was studied with regard to animal mortality, morbidity, myocardial pathologic features and myocardial beta-adrenergic adenylate cyclase activity. Verapamil administration dramatically decreased the mortality rate from 60% to 6% during the 70 day period of infection. Three clinical stages of infection were evident. In the acute stage (17 days after infection with maximal parasitemia), verapamil treatment not only decreased the incidence of myocardial disease (fibrosis and inflammation), but also protected myocardial beta-adrenergic adenylate cyclase activity. In addition, there was no increase in total body weight, which was regarded as an index of right-sided heart failure. In the subacute stage (30 to 60 days after infection), administration of verapamil continued to decrease myocardial disease and preserve beta-adrenergic adenylate cyclase activity. In addition, verapamil ameliorated the morbidity and mortality associated with this stage of infection. The chronic stage of infection was characterized by a decrease in myocardial disease and in beta-adrenergic adenylate cyclase activity. Thus, independent of the state of infection, long-term verapamil treatment enhanced beta-adrenergic adenylate cyclase activity. In addition, verapamil ameliorated the morbidity associated with infection. Although the relation among these various effects of verapamil in the setting of T. cruzi infection remains to be determined, collectively the results suggested that verapamil administration attenuated the consequences of T. cruzi infection.     

范可尼综合征的临床特点与生化异常

目的 进一步认识范可尼综合征（FS）的病因、临床特点与生化异常。方法 对我院确诊的42例FS患者进行回顾性分析。结果 42例FS中完全型19例,不完全型23例,主要表现为近端肾小管酸中毒（41例）伴物质转运异常,包括低钾血症（21例）、低磷血症（29例）、低尿酸血症（19例）、肾性糖尿（38例）、氨基酸尿（36/37例）和低分子蛋白尿（21例）。病因：特发性或原因不明21例,继发性21例;其中间质性肾炎8例,干燥综合征5例。临床表现以乏力、多饮、多尿、肾性骨病最常见,伴肾功能不全者18例。14例患者接受肾活检,结果均显示有不同程度的小管-间质病变,其中4例伴有肾小球病变。结论 FS病因多样,继发性FS并不少见,一般均伴有Ⅱ型肾小管酸中毒,并常有肾小管-间质的病理损害。     

Gout: diagnosis, pathogenesis, and clinical manifestations

Gout is a common form of arthritis, in which many of the risk factors, pathogenetic mechanisms, and clinical features have been recognized for years. Nevertheless, new information has become available regarding the normal physiologic role of uric acid as an antioxidant, and greater insight has been obtained regarding the inflammatory process in acute gout. New studies have improved our understanding of the role of genetic and environmental factors responsible for hyperuricemia, and we know more about the significance of the association of hyperuricemia with other diseases. Clinically, rare complications and disease manifestations in new populations continue to be discussed, and diagnostic methods continue to be refined.     

Growth hormone and HIV infection: contribution to disease manifestations and clinical implications

In untreated HIV patients growth hormone deficiency contributes to loss of lean and fat mass. Pharmacologic doses of growth hormone successfully reverse this wasting process. In patients responding to antiretroviral therapies several non AIDS-related complications usually common among older, uninfected persons now occur more frequently in younger HIV patients. Among these conditions are cardiovascular disease and metabolic disorders. Although their etiology is multifactorial, changes in growth hormone biology reflecting relative growth hormone deficiency occur and may be involved. In these patients truncal obesity, and associated dyslipidemia and glucose homeostasis changes contribute to impaired quality of life and increased cardiovascular risk. Treatment with growth hormone and growth hormone releasing factor leads to short-term improvement of some of these abnormalities. This paper will review abnormalities of growth hormone biology and the use of growth hormone and growth hormone releasing factor as therapeutic agents in HIV patients.     

Sarcoidosis: clinical manifestations, epidemiology, therapy, and pathophysiology

Sarcoidosis is an idiopathic granulomatous disease involving one or more multiple organ systems, characterized by the histologic finding of noncaseating epithelioid cell granulomas. The disease has a predilection for intrathoracic structures; the musculoskeletal system is less frequently involved. Most osseous lesions in sarcoidosis are visible in the small joints of the hands and feet. Articular disease may present as an acute or chronic polyarthritis. Muscle involvement in sarcoidosis is generally asymptomatic. Neurologic findings of the central and peripheral nervous systems may occur in sarcoidosis. Subcutaneous nodules are of diagnostic value. Sarcoid vasculitis may involve small and large blood vessels. Sarcoidosis of the exocrine glands may mimic Sj?gren's syndrome. Spontaneous remission of disease often occurs. Treatment with nonsteroidal anti-inflammatory agents, corticosteroids, antimalarials, radiation therapy, and immune-modulating drugs may be beneficial in the treatment of sarcoidosis.     

Scrub typhus: pathophysiology,clinical manifestations and prognosis

Scrub typhus is a zoonosis caused by the pathogen Orientia tsutsugamushi (O. tsutsugamushi). The disease has significant prevalence in eastern and Southeast Asia. Usually presenting as an acute febrile illness, the diagnosis is often missed because of similarities with other tropical febrile infections. Many unusual manifestations are present, and these are described in this review, together with an outline of current knowledge of pathophysiology. Awareness of these unusual clinical manifestations will help the clinician to arrive at an early diagnosis, resulting in early administration of appropriate antibiotics. Prognostic indicators for severe disease have not yet been clearly established.