The correct answer is 5. The mother should be isolated for the first 2-4 weeks of treatment, after which she would no longer be contagious. If the result of the repeat PT is still negative, the child should not be tested again. If it is positive, the X-ray (or pulmonary CT in younger children) should be repeated.

The [HIDDEN] The mother should be isolated for the first 2-4 weeks of treatment, after which she would no longer be contagious. If the result of the repeat PT is still negative, the child should not be tested again. If it is positive, the X-ray (or pulmonary CT in younger children) should be repeated.

A 1-year-old boy whose mother has just been diagnosed with bacilliferous pulmonary tuberculosis, having started correct treatment. The child is asymptomatic with a normal examination, negative tuberculin test (PT) and normal chest Rx. What would be the attitude to adopt in the child?

Only separate him from the mother until her treatment is completed (at least 6 months).

Perform a high-resolution CT scan of the lung, and if normal, repeat PT at 8-12 weeks.

Chemoprophylaxis with isoniazid (INH) until the mother's smear test is negative.

Chemoprophylaxis with INH 6-9 months. New PT and chest X-ray at the end of treatment, to decide whether or not to conclude treatment.

Chemoprophylaxis with INH, 8-12 weeks. Repeat PT. If negative, stop treatment. If positive, perform chest X-ray to decide whether or not there is disease.

[Tuberculosis in the mother and child].

Tuberculosis is a scourge in our region; it is particularly dangerous in young children, above all those of tuberculous mothers. The object of this study is to evaluate the prevalence of tuberculosis in the children of tuberculous mothers and to determine how to increase their chances of survival and healthy development. Between 1 January and 31 July 2002, 45 women were admitted to hospital with a child of less than 5 years. They received (mothers and children) an intradermal tuberculin test (IDTT) of 10 i.u., chest x-ray, and sputum examination for the mothers. 45 women (aged from 18 to 45 years) were hospitalised for sputum positive tuberculosis, an average IDTT of 13 mm and a high bacterial load (1 to>10 bacilli/hpf). Almost all (96%) presented with cavitating parenchymatous disease. We found no cases positive for HIV. Progress was satisfactory in 43 mothers treated with SRHZ. There were 2 deaths. In the children who were systematically examined, 82% (37) were less than 20 months old, there were 23 boys (51%), and 26 children (58%) were symptomatic at the first consultation. All the children were breast fed, explaining their admission with their mother. Evidence of tuberculous contact was found, 6 times with the father and 4 times with the grandparents. The most common physical signs were fever (92%) cough and weight loss (77%), malnutrition (69%). The IDTT was positive in 38/45 (84.5%) and pustular in 16/38 (42%). The chest x-ray was normal in 16/45 (35.6%), revealed mediastinal adenopathy in 19/29 (65.5%), accompanied by ipsilateral ventilatory problems in 11/29 (38%) and by parenchymal involvement in 3/29 (10.3%). Progress was satisfactory in 44 children on antituberculous treatment (RHE). There was one death on account over severe malnutrition. Treatment of tuberculosis in the mother and child is a guarantee of recovery for the mother and healthy development for the child. S: streptomycin, R: rifampicin, H: isoniazid, E: ethambutol, Z: pyrazinamide.

[Should pulmonary computed tomography be performed in children with tuberculosis infection without apparent disease?].

During early childhood, in particular, there is a continuum between tuberculosis infection and disease. When establishing the diagnosis in a child with suspected tuberculosis, the distinction between infection and disease frequently depends on the interpretation of the chest X-ray. Some studies have shown hilar and mediastinal lymphadenopathies on computed tomography (CT) in children with tuberculosis infection without apparent disease, i.e., asymptomatic children with a positive tuberculin skin test and normal chest X-ray. These observations raise the issue of whether pulmonary CT should be performed in children with tuberculosis infection without apparent disease and whether different types of therapy should be administered depending on the results. We reviewed the physiopathology of tuberculosis infection and disease, diagnostic methods and treatment, and the literature on the use of pulmonary CT scan in pediatric tuberculosis. Modern CT scanners indicate hilar and mediastinal lymphadenopathies in many of the children with tuberculosis infection with no apparent disease on chest X-rays. However, neither the size nor the morphology of these adenopathies allows active tuberculosis to be diagnosed. The natural history of childhood tuberculosis indicates that most children show hilar lymphadenopathies after the primary infection, although progression to disease is rare and is characterized by the presence of clinical symptoms. The exceptions are children younger than 4 years old and those with immune alterations who more frequently show progression of infection to disease and who require close follow-up. In addition, the experience accumulated over many years in the treatment of tuberculosis infection with isoniazid has shown this drug to be effective in both short- and long-term prevention of active disease. Official guidelines and expert opinion do not recommend systematic pulmonary CT scan in these children or modification of treatment according to the results. Hilar and mediastinal lymph nodes are frequently found in the CT scans of children with tuberculosis infection without apparent disease but there is no evidence that these adenopathies indicate active disease or that these children require different treatment. Consequently, until demonstrated otherwise, pulmonary CT scanning and changes in chemoprophylaxis are not justified in children with tuberculosis infection.

[Chemotherapy of the source and the risk of infection in home contacts].

An attack treatment with 3 drugs during 4-6 months and a consolidation treatment with 2 drugs then INH was applied in 595 cases detected between July 1, 1968 and June 30, 1972, i.e. 264 group A (positive), 200 group B (negative cultures) and 131 group C (pleuretics). The contacts had been in close contact with the source for at least three months before establishing the diagnosis; 549 had been vaccinated at birth with BCG and 209 revaccinated; 413 had undergone chemoprophylaxis with INH.  The control group comprised 1008 subjects, the mean age of the groups being very close; they were followed up for 2 years and 1 month and 2 years and 7 months.  Testing was done every year with 1 u PPD IC 65. The contacts were controlled annually by radiophotography and X-ray and the controls only in case of shifting of the test. Among the contacts there were 44 conversions in the subjects with an initial tuberculin reaction of 0-5 mm and 4 in those with an initial tuberculin reaction of 6-9 mm, representing 15.1% (group A 27.7%, group B 9,8%, group C 10.5%). Three months after the initiation of chemotherapy the proportion of conversions in the three groups (group A 12.3%, group B 5.9%, group C 10.5%) was equal to that of the controls (8.8%). The next year there were 11.2% conversions among the contracts (group A 11.4%, group B 9.6% and C 17.7%) as against 11.9% among the controls. In the first year 8.3% of the contacts contracted tuberculosis (A 15.6%, B 2.4%, C 4.0%) and 0.32% of the controls. The next year 2.8% of the  contacts fell ill (A 4.3%, B 2%, C 0%) and 0.5% of the controls. Among group A contacts aged 0 to 6 years there were 31.7% conversions and 30.7% cases of tuberculosis in the first year, and 7.1% and 1.8% respectively in the following year. Group B and C presented 10.9% conversions and 6% cases of disease in the first year, and no case of tuberculosis in the second year. Chemotherapy reduced conversions and sickness in this group three months after the diagnosis was established.

Lack of adherence to isoniazid chemoprophylaxis in children in contact with adults with tuberculosis in Southern Ethiopia.

Hawassa, Southern Region of Ethiopia. To determine compliance to isoniazid (INH) preventive therapy (IPT) and its effectiveness in preventing (TB) disease in children in contact with adults with pulmonary TB (PTB). This was a prospective cohort study of children <15 years old in contact with adults with smear-positive PTB. Asymptomatic children ≤5 years were provided IPT independently of their Tuberculin Skin Test (TST) status and children >5 years old were given advice but did not receive IPT, as recommended by the National TB control programme. Compliance to IPT and incidence of clinical TB were determined monthly for six months and then quarterly for up to 30 months. One hundred and eighty four children in contact with 83 smear-positive PTB cases were identified. Eighty two were ≤5 and 102>5 years old. Only 27 (33%) of 82 children given IPT took it for >4 months and 10 (12%) completed the 6-month course. The main reason for non-compliance was the perception that drugs were not necessary when the child was healthy. Eleven children (all except one >5 years old) developed symptoms of TB disease and initiated treatment, resulting in an incidence of 28.6 cases for all and 53.5 for children >5 years old per 1000 children-year. Compliance to IPT in children is poor in Southern Region of Ethiopia and this was associated with the parents' perception of the low importance of chemoprophylaxis in asymptomatic children. Poor compliance might be an important barrier for the wider implementation of IPT. Clinicaltrials.gov NCT00456469.

Tuberculosis in children and its management.

Children with tuberculosis (TB) in the United States are generally asymptomatic, 60% are under 5 years, 80% belong to racial/ethnic minorities or are foreign born, and most are diagnosed during the investigation of contacts of known cases of pulmonary TB. A presumptive diagnosis of primary TB is made on the basis of a positive tuberculin reaction and a characteristic chest roentgenogram, usually showing hilar adenopathy. Treatment may be with isoniazid (INH) and rifampin (RIF), largely twice weekly for 9 months, or INH, RIF, and pyrazinamide for 2 months followed for 4 months by INH and RIF. Four drugs are needed in cases of infection with drug-resistant organisms or in tuberculous meningitis. All therapy must be closely monitored for toxicity and compliance. In noncompliant families, all medication should be directly administered. This is now possible with short-course therapy, largely twice weekly. Preventive therapy for the tuberculin positive, but disease-free child, is provided more cost-efficiently with 6 months than with 12 months of treatment with INH; less than 6 months is not adequate. All tuberculin reactive children should receive INH for 6 months. More diligence in providing INH prophylaxis to adult reactors will decrease future infectious TB cases, and thus prevent transmission to other children.

Latent tuberculosis

A person who has taken the complete course of Isoniazid (or other full course prescription for tuberculosis) on a regular, timely schedule may have been cured. "Current standard therapy is isoniazid (INH) which reduce the risk of active TB by as much as 90 per cent (in patients with positive LTBI test results and fibrotic pulmonary lesions compatible with tuberculosis) if taken daily for 9 months." [Emphasis added] However, if a person has not completed the medication exactly as prescribed, the "cure" is less likely, and the "cure" rate is directly proportional to following the prescribed treatment specifically as recommended. Furthermore, "[I]f you don't take the medicine correctly and you become sick with TB a second time, the TB may be harder to treat if it has become drug resistant." If a patient were to be cured in the strictest definition of the word, it would mean that every single bacterium in the system is removed or dead, and that person cannot get tuberculosis (unless

Latent tuberculosis

There are several treatment regimens currently in use: 9H — isoniazid for 9 months is the gold standard (93% effective, in patients with positive test results and fibrotic pulmonary lesions compatible with tuberculosis). 6H — Isoniazid for 6 months might be adopted by a local TB program based on cost-effectiveness and patient compliance. This is the regimen currently recommended in the UK for routine use. The U.S. guidance excludes this regimen from use in children or persons with radiographic evidence of prior tuberculosis (old fibrotic lesions) (69% effective). 6 to 9H2 — An intermittent twice-weekly regimen for the above 2 treatment regimens is an alternative if administered under Directly observed therapy (DOT). 4R — rifampicin for 4-months is an alternative for those who are unable to take isoniazid or who have had known exposure to isoniazid-resistant TB. 3HR — Isoniazid and rifampin may be given daily for three months.

[Active tuberculosis in children who received INH chemoprophylaxis].

Twelve children who developed active tuberculosis even after receiving isoniazid (INH) chemoprophylaxis were seen at Tokyo Metropolitan Children's Hospital from 1982 through 1991. All cases received INH more than 9 mg/kg/day, except for one case in which the amount of INH administered at the referring hospital was unknown and Streptomycin was administered together with INH. The age of starting INH prophylaxis ranged from 2 months to 13 years, and the age at which clinical symptoms and/or laboratory evidences of active tuberculosis were first manifested ranged from 4 months to 18 years. Five patients developed active tuberculosis after the completion of chemoprophylaxis and patients during chemoprophylaxis, with the first presentation ranging from primary complex (seven), chronic pulmonary tuberculosis (two), tuberculous meningitis (two), and tuberculous pleuritis (one). None of the Mycobacterium tuberculosis resistant to INH was isolated. Reviewing these patients, eleven cases had at least one of the following factors: (1) age less than two years old (2) infectious sources expectorated more Mycobacterium tuberculosis (3) delay in starting INH. Above factors should be considered in initiating INH chemoprophylaxis and subsequent follow-up of the patients.

Latent tuberculosis

Evidence for treatment effectiveness A 2000 Cochrane review containing 11 double-blinded, randomized control trials and 73,375 patients examined six and 12 month courses of isoniazid (INH) for treatment of latent tuberculosis. HIV positive and patients currently or previously treated for tuberculosis were excluded. The main result was a relative risk (RR) of 0.40 (95% confidence interval (CI) 0.31 to 0.52) for development of active tuberculosis over two years or longer for patients treated with INH, with no significant difference between treatment courses of six or 12 months (RR 0.44, 95% CI 0.27 to 0.73 for six months, and 0.38, 95% CI 0.28 to 0.50 for 12 months).

InternalMed_Harrison

It is estimated that about 2 billion people, or nearly one-third of the human population, have been infected with M. tuberculosis. Although only a small fraction of these infections will progress toward active disease, new active cases will continue to emerge from this pool of “latently” infected individuals. Unfortunately, there is no diagnostic test at present that can predict which individuals with LTBI will develop active TB. Treatment of selected persons with LTBI aims at preventing active disease. This intervention (also called preventive chemotherapy or chemoprophylaxis) is based on the results of a large number of randomized, placebo-controlled clinical trials demonstrating that a 6to 9-month course of isoniazid reduces the risk of active TB in infected people by up to 90%. Analysis of available data indicates that the optimal duration of treatment is ~9 months. In the absence of reinfection, the protective effect is believed to be lifelong. Clinical trials have shown that

Tuberculosis management

A 2000 Cochran review containing 11 double-blinded, randomized control trials and 73,375 patients examined six and 12 month courses of isoniazid (INH) for treatment of latent tuberculosis. HIV positive and patients currently or previously treated for tuberculosis were excluded. The main result was a relative risk (RR) of 0.40 (95% confidence interval (CI) 0.31 to 0.52) for development of active tuberculosis over two years or longer for patients treated with INH, with no significant difference between treatment courses of six or 12 months (RR 0.44, 95% CI 0.27 to 0.73 for six months, and 0.38, 95% CI 0.28 to 0.50 for 12 months).

Tuberculosis in neonates and infants: epidemiology, pathogenesis, clinical manifestations, diagnosis, and management issues.

Tuberculosis is one of the leading infectious causes of death and as such represents a major global health problem. Infants may develop congenital tuberculosis from an infectious mother or, most commonly, they may acquire postnatal disease by contact with an infectious adult source. Important epidemiologic, pathogenetic, and clinical data regarding the management of infantile disease are reviewed. Diagnostic evaluation includes tuberculin skin tests, chest radiography and other imaging studies, smears and cultures, examination of the cerebrospinal fluid, and polymerase chain reaction, as well as the more recent interferon-gamma assay. Pregnant women with a positive Mantoux skin test but normal chest x-ray should either start chemoprophylaxis during gestation or after delivery depending on the likelihood of being recently infected, their risk of progression to disease, as well as their clinical evidence of disease. Pregnant women with a positive Mantoux skin test and chest x-ray or symptoms indicative of active disease should be treated with non-teratogenic agents during gestation; all household contacts should also be screened. When tuberculosis is suspected around delivery, the mother should be assessed by chest x-ray and sputum smear; separation of mother and offspring is indicated only if the mother is non-adherent to medical treatment, needs to be hospitalized, or when drug-resistant tuberculosis is involved. According to the American Academy of Pediatrics, treatment of latent infection is highly effective with isoniazid administration for 9 months. This regimen may be extended to 12 months for immunocompromised patients. When drug resistance is suspected, combination therapies, which usually consist of isoniazid with rifampin (rifampicin), are administered until the results of susceptibility tests become available. Organisms resistant to isoniazid only may be treated with rifampin alone for a total of 6-9 months. All infants with tuberculosis disease should be started on four agents (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) until drug susceptibility is assessed. For susceptible intrathoracic tuberculosis, isoniazid, rifampin, and pyrazinamide are administered for a total of 2 months, at which point pyrazinamide is withdrawn and the other two agents are continued for another 4-10 months depending on the severity of the disease. The same regimen may be applied in extrapulmonary tuberculosis with the exception of skeletal, miliary, and CNS disease, which require daily administration of isoniazid, rifampin, pyrazinamide, and streptomycin for 1-2 months, followed by isoniazid and rifampin daily or twice weekly for another 10 months. When drug-resistant tuberculosis is suspected, a regimen of isoniazid, rifampin, and pyrazinamide plus either streptomycin or ethambutol should be initially prescribed, until the results of susceptibility tests become available. HIV-seropositive infants with pulmonary tuberculosis should receive isoniazid, rifampin, pyrazinamide, and ethambutol or an aminoglycoside for 2 months, followed by isoniazid and rifampin for a total of at least 12 months. Apart from conventional antimycobacterial agents, novel therapeutic modalities, which stimulate the host immune system such as interleukin-2 (IL-2), IL-12, interferon-gamma, and tumor necrosis factor antagonists have been tested with promising results.

Adherence to and outcome of isoniazid chemoprophylaxis among household contact children of adults having pulmonary tuberculosis in Alexandria, Egypt.

Current international guidelines recommend 6-9 months of isoniazid (INH) preventive chemotherapy to prevent the development of active tuberculosis (TB) in susceptible children exposed to Mycobacterium tuberculosis. However, this is dependent on good adherence, as shown by previous studies. This study was conducted to describe the outcome of screening of contact children aged 5 years or less with household exposure to an adult pulmonary TB index case to determine the prevalence and possible risk factors of infection among contact children and to determine the extent and outcome of adherence of contact children to unsupervised INH chemoprophylaxis for 6 months. A descriptive facility-based cross-sectional study was conducted from March 2009 to August 2010. Research settings were three of the National TB control program chest dispensaries (primary care facilities) in Alexandria, Egypt. Facility-based TB treatment registers of the previous 3 months were used to identify all new adult pulmonary TB cases. All children aged 5 years or less living in the same house as the index cases were identified and screened for TB. The contact children were given unsupervised INH preventive chemotherapy once active TB was excluded. Adherence to and outcome of preventive chemotherapy were followed up. Preventive chemotherapy consisted of unsupervised INH monotherapy for 6 months with monthly collection of tablets from the clinic. Adherence was documented after completion of the 6-month preventive treatment period. Adherence was considered reasonable if tablets were collected for more than 4 months, poor if collected for 2-4 months, and very poor if collected for less than 2 months. (a) Prevalence of infection and disease and the possible risk factors among contacts. (b) The extent and outcome of adherence to unsupervised INH chemoprophylaxis among contact children. (c) Factors behind poor adherence. In total, 197 adult TB index cases from 187 households were identified. In all, 297 children aged 5 years or less experienced household exposure, of whom 252 (84.9%) were fully evaluated. Tuberculin test was positive in 136 of the 252 child contacts (54.0%), of whom 130 were contacts of sputum-positive patients and six were contacts of sputum-negative patients. The important risk factors for transmission of TB infection were younger age, male sex, severe malnutrition, absence of BCG vaccination, contact with a sputum-positive adult who was a source case, household overcrowding, and exposure to environmental tobacco smoke. Thirty-three children were diagnosed and treated for TB at the baseline screening and 217 received preventive INH chemotherapy. Of the children who received preventive chemotherapy, only 36 (16.6%) completed at least 4 months of unsupervised INH monotherapy. During the subsequent follow-up period, eight children developed TB (secondary attack rate for TB disease was 3.7%), of whom four received no preventive chemotherapy and four were poorly adherent. The prevalence of TB infection and clinical disease among children in household contact with adult patients is high, and risk is significantly increased because of child contact, index patients and environmental factors. Adherence to 6 months of unsupervised INH chemoprophylaxis was very poor.

[Efficacy of tuberculosis contacts investigation and treatment, especially of preventive therapy in infants and young children].

Although large clinical trials reported in 1960s suggested that preventive therapy in subjects with tuberculosis (TB) infection reduces the risk of developing TB by 70-90%, the therapy in our TB clinic seems to be more effectiveness. We retrospectively evaluated the efficacy of the present contacts investigation, especially of preventive therapy for further improvement of TB control for children. We examined 273 asymptomatic infants and children younger than five years who had household contacts with active TB patients and visited our clinic for contact investigation. After the diagnosis at the first visit to our TB clinic, they were treated and/or observed for at least two years to assess whether contact investigations and following treatment are appropriate. Since infants less than a year are underdeveloped in cell-mediated immunity and their tuberculous lymphadenopathy can be overlooked on standard chest radiographs, chest CT scans were added. At their first visit, 60 (22%) out of 273 subjects were diagnosed as TB, and 37 (14%) were suspected as TB. We treated them by combinations of anti-TB medicines including isoniazid and rifampin for six to 12 months, and they did not relapse during the observation period. Twenty-six subjects (9%) were diagnosed uninfected. However, a three-year-old girl developed bilateral hilar lymphadenopathy two months later when the reexamination was done. A hundred and fifty subjects (55%) were diagnosed to have TB infection. They received preventive therapy with isoniazid (10 mg/kg/day) for six months. Among them, a four-month-old boy developed TB disease soon after starting to take isoniazid and was treated by the combination of anti-TB medicines. Other 149 subjects completed the therapy, and none of them developed disease during the observation period. There was no increase in serum GOT and/or GPT to > 100 IU/L within one month after starting to take isoniazid. The present contacts investigations and treatments in our TB clinic are useful ways to find out and control TB diseases and infections, and it might be suggested to start the six-months preventive therapy after active TB has been ruled out in all infants and children who had close contacts with active TB patients for preventing TB disease and latent TB infection in the future even their clinical and laboratory examinations do not suggest infection.

Outcome of neonates exposed to active pulmonary tuberculosis.

To determine the incidence of tuberculosis infection and disease in neonates exposed to an active pulmonary tuberculosis patient in a nursery and maternity ward. Descriptive cohort study was carried out in Srinagarind Hospital, Khon Kaen University, North-East Thailand. A smear positive pulmonary tuberculosis mother with productive cough was diagnosed on the fifth day of admission. The authors urged parents of all exposed neonates to accept isoniazid (INH) prophylaxis for their infants for six months. All neonates underwent chest x ray (AP, lateral view) and tuberculin skin test on the 24 months follow-up. The 48 neonates were identified as exposed. The age of follow-up ranged from 30 to 32 months. Only three were lost to follow-up. Of the remaining 45 neonates, six refused to take INH prophylaxis. Complete six months of LNH prophylaxis were observed in 27 (60%) of 39 contacts. Tuberculin skin tests (TST) were performed in all of 45 contacts. No cases were positive for TST. Abnormal chest radiographies were found in nine of INH group, three patients had hilar lymphadenopathy and six had pneumonia. The repeat chest x ray, two weeks later was normal in all cases. After 30 to 32 months follow-up, none of the 39 neonates who received INH prophylaxis or the six neonates progressed to have active tuberculosis. In exposed neonate identified as the high-risk group, appropriate INH prophylaxis, and long-term follow-up, especially in the first-2 years, seemed to be effective in preventing the development of active tuberculosis.

InternalMed_Harrison

DOTS was clearly effective for most uncomplicated cases of drug-susceptible TB, but a number of shortcomings were soon identified. First, the diagnosis of TB based solely on sputum smear microscopy— a method dating from the late nineteenth century—is not sensitive. Many cases of pulmonary TB and all cases of exclusively extrapulmonary TB are missed by smear microscopy, as are most cases of active disease in children. Second, passive case-finding relies on the availability of health care services, which is uneven in the settings where TB is most prevalent. Third, patients with multidrug-resistant TB (MDR-TB) are by definition infected with strains of Mycobacterium tuberculosis resistant to isoniazid and rifampin; thus exclusive reliance on these drugs is unwarranted in settings in which drug resistance is an established problem.

Smear-negative pulmonary tuberculosis.

Diagnostic difficulties arise when sputum smears are negative for acid-fast bacilli in tuberculin-positive patients with compatible symptoms and chest radiographs for tuberculosis. Many of these smear-negative patients yield positive cultures for M tuberculosis, whereas others remain culturally negative. Several studies have shown that many smear-negative/culture-negative patients will develop bacteriologically positive disease later. Often, physicians are unable to decide whether to initiate chemotherapy or to wait for the culture results. Also, if treatment is initiated in smear negative patients, what should be the drug regimen and duration of therapy. A positive smear signifies a very large bacterial population in the lung lesions whereas several negative smears suggest a smaller bacterial load. Such smear-negative cases do not require the same intensity and duration of treatment as smear-positive cases. Therapy should be initiated for tuberculosis after other causes for abnormal chest x-ray have been excluded. However, duration of therapy may be shortened in these cases. The British Medical Research Council (BMRC) study has shown that intensive treatment of smear-negative/culture-positive disease with streptomycin (SM), isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) for 4 months was uniformly successful. This regimen is routinely recommended in Hong Kong. Because primary drug resistance is low (< 3%) in Arkansas, we treated these cases with INH and RIF for 6 months with good results. This is now a routine drug regimen. For smear-negative/culture-negative cases, the BMRC study has shown that daily or thrice weekly treatment with SM, INH, RIF, and PZA for 4 months is effective.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effectiveness of isoniazid in tuberculosis chemoprophylaxis in children with rising tuberculin sensitivity].

70 children aged 4-15 with growing tuberculin sensitivity received preventive treatment with isoniazid in children's sanatorium. The drug was taken for 2 or 3 months in a dose 10 mg/kg daily (19 and 51 children, respectively). Preventive isoniazid course proved effective as none of the children treated developed tuberculosis within 3 years. The 3-month course is preferable as it is more potent in relation to tuberculin sensitivity immediately after the treatment termination and 1, 2 years after it.

[Tuberculosis in patients after kidney transplantation].

Infection caused by Mycobacterium tuberculosis is common among population in Poland. We analyzed the effect of tuberculosis (TB) on patients and graft survival in the group of renal allograft recipients (RAR), treated in our center. Among 1669 renal allograft recipients transplanted from 1981 to 1992, tuberculosis developed in 33 (2%) patients (16 M/17F, age: 22-57 years). The patients were on following immunosuppressive regiments" Pred+Aza+CsA (12 pts), Pred+Aza (12), Pred+CsA (6) and Pred+Aza+CsA+ATG (3). Acute rejection was diagnosed in 27 of them and was treated with methyloprednisone pulses, and in a few cases additionally with ATG (2 pts) or OKT3 (1 pt). In two pts TB had been diagnosed and successfully treated in the past. In 6 pts, on chest X-ray done immediately before transplantation, healed primary lesion (Ghon complex) had been seen. In 16 pts TB developed in the early posttransplant period (median: 3.8 +/- 1.8, range: 1-6 months) and in 17--late after transplantation (median: 31.2 +/- 1.8, range: 13-156 months). In 19 pts symptoms developed soon after treatment of acute rejection. Clinical manifestations include pulmonary TB (30 pts) and extrapulmonary lesions (15 pts): pleural TB (3 pts), miliary TB (5 pts), tuberculous lymphadenitis (1 pt), uveitis (1 pt), renal allograft (2 pts), skeletal (2 pts) and GI tract (1 pt). Diagnosis of TB was made based on clinical presentation and radiologic findings and it was confirmed by positive cultures in 18 pts, by tissue biopsy in 4 pts and by autopsy examination in 9 pts. Treatment regimen included one of the following drug combinations: INH+EMB+RMP (20 pts), INH+RMB+RMP+PZA (10 pts) or INH+EMB+SM (3 pts). Three pts died before TB was recognized and 4 deaths occurred after treatment was started. All these pts developed renal failure. 26 pts were treated for 3-12 months (median, range: 7.8 +/- 2.9) and in 24 of them complete remission was achieved. In this group renal function remained stable in 16 pts and 6 pts developed terminal failure due to chronic rejection. Authors conclude: 1. TB remains a frequent complication in RAR but can be successfully treated when diagnosed early. 2. Extrapulmonary TB is common in RAR. 3. TB deteriorates one year patients (75%) and graft (49%) survivals.

[Tuberculosis: diagnosis of contact persons and chemoprophylaxis in children].

Every doctor must participate in each step of tuberculosis control including BCG vaccination and focused screening, diagnosis of contact subjects. The last is mandatory in children, due to rapid ongoing illness from primary infection (PI). The two strategies of management are the search for secondary cases around a recently diagnosed contagious tuberculosis and the search for a contaminator in front of a recent PI or illness in a child. To suppress the anonymity of notification helps. The screening relies on a "stone in the water" strategy, from close to more occasional contacts. The search for contaminators (family, collectivity) relies on chest radiography (CR) and if positive, is extended to the contaminated surroundings. The search for secondary cases relies on tuberculin intra-dermal test (IDR); if positive, a CR is asked for and always performed in aged or immunodepressed persons, and children under 5 years of age. For them, a thoracic scan is easily done because of small mediastinal adenopathies undiagnosed by plain CR. Despite imperfect sensitivity and specificity, IDR is pivotal for diagnosis in children. Any PI in children has to be treated. In France, bitherapy isoniazide-rifampicine is given before 3 years of age and often up to 10 years. A duration of 6 months is common. Patent forms receive a tri or quadri-therapy for the first 2 months followed by a 4 months bitherapy. A cornerstone of success is an adequate organisation and coordination of motivated health care workers.

Preventing tuberculosis in children receiving anti-TNF treatment.

Anti-tumor necrosis factor (TNF) treatment has been a breakthrough in the management of juvenile idiopathic arthritis (JIA). However, they are associated with a significant risk of tuberculosis. We evaluated JIA patients who received etanercept treatment from an eastern Mediterranean country with moderate tuberculosis frequency. JIA patients under anti-TNF treatment, etanercept, were enrolled to the study. Chest X-rays, Tuberculin Skin Test (TST), clinical histories, family screening, and physical examinations were reviewed retrospectively. If TST was above 10 mm in a patient with one Bacillus Calmette-Guerin, cultures and, if needed, thorax computerized tomography were obtained. These patients received 1-2 months of isoniazid (INH) treatment which was followed by an INH prophylaxis for a period of 9 months while etanercept treatment was started. All were re-evaluated within 3 months intervals. A total of 36 patients under etanercept treatment were enrolled to the study. Mean age of the patients was 14.00 years (range 4-22 years). Median duration of disease was 36.00 months (range 4-216 months). Median duration of etanercept therapy was 11.5 months (3-48 months) at final evaluation. Seven patients had an initial TST score above 10 mm. All received INH treatment as outlined above. They had normal examinations and X-rays during followup. With proper initial evaluation, anti-TNF treatment is safe even in countries where tuberculosis is moderately frequent. An initial 1-2 months of INH treatment followed by chemoprophylaxis for 9 months is suggested for children with a TST of >10 mm.

[Yield from studying the contacts of patients with tuberculosis].

Between march '88 and august '89 a total number of 437 contacts (CT) with 69 patients with tuberculosis were analyzed. According to the bacteriological status of the index case the observations were distributed into: Group I (197) CT with patients with positive sputum AFB stain test; Group II (24) CT with cases with positive sputum culture but negative AFB stain; and Group III (216) CT with cases with histologic diagnosis or cases in children. Following identical criteria and according to the bacteriologic situation of the Source case, we grouped the contacts on groups A (246), B (17), and C (174). A clinical history, thorax radiography, and tuberculin test with 2 UT of PPD-RT 23 were performed in all CT cases. Tuberculin reaction was equal or greater than 6 mm in 45% (88/197), 25% (6/24), and 36% (77/216) of groups I, II, and III respectively. This reaction was also positive in 49% (121/246), 23% (4/17), and 26% (46/174) of groups A, B, and C respectively. Sixteen new cases of tuberculosis were discovered among which we identified 5 new source cases. A second tuberculin test was performed in 44% (116/266) of CT with a previous negative test, and in this population we observed 16 conversions. It is demonstrated: 1) a high yield in the detection of infection/tuberculous disease; 2) the analysis of CT in group A provided the highest index of tuberculous infection, and 3) revision of CT of groups II and III provided most of the new cases of disease as well as the identification of 5 new source cases.

Variability in the intradermal and in vitro lymphocyte responses to PPD in patients receiving isoniazid chemoprophylaxis.

Much attention has been focused on problems related to the interpretation of the tuberculin (Tb) skin test in terms of the "booster" phenomenon observed with repeated skin testing. However, relatively little attention has been given to the problem of the interpretation of repeat Tb skin tests in patients who have been given isoniazid (INH) chemoprophylaxis. Sixteen female hospital workers who were receiving INH for asymptomatic recent conversion of their Tb skin test, and 1 male physician under treatment with INH and rifampin for active tuberculosis as a result of a patient exposure, were studied over a 1-yr period. Intradermal skin tests with 5 tuberculin units purified protein derivative (PPD) and assessment of in vitro lymphocyte proliferation and production of leukocyte inhibitory factor on exposure to PPD were performed on 4 occasions at 3-month intervals-3 during therapy and 1 after completion of therapy. Four of 10 patients tested on all occasions showed at least 1 negative Tb skin test. In 2 of 4, the reversions were not stable. Considerable variability was observed between results of skin tests and in vitro lymphocyte responses, and no one in vitro lymphocyte response to PPD was adequate to identify the presence of delayed hypersensitivity to PPD. On the basis of these data, it is concluded that the presence of a single negative PPD skin test during or shortly after the completion of INH chemoprophylaxis does not constitute sufficient evidence to conclude that a patient has had a stable skin test reversion. Confirmation of the loss of tuberculin reactivity requires the in vitro assessment of lymphocyte responses to PPD both in terms of proliferation and the production of a lymphokine(s).

[Chemoprophylaxis of tuberculosis].

Chemoprophylaxis of tuberculosis may be primary or secondary. Primary chemoprophylaxis is intended for infants and children with negative tuberculin tests and exposed to contagion, in order to avoid primary tuberculosis. It lasts for three months and consists of oral isoniazide in one single daily dose of 5 to 10 mg/kg. Secondary chemoprophylaxis applies to all subjects, but principally to children, with a tuberculin test that has recently become positive in the absence of BCG vaccination. Its purpose is to protect against clinical tuberculosis. It lasts for six months and consists of isoniazid combined with rifampicin.

[Outbreak of pulmonary tuberculosis in which tuberculosis developed from QuantiFERON-TB second generation (QFT-2G) test negative persons].

To clarify the points to be considered when QFT-2G tests are used in the contacts examination by public health center. We analyzed the results of contacts examination on 43 workplace colleagues (39 y/o and younger) of a pulmonary tuberculosis patient (bII2, Gaffky 9, cough for 1.5 months). After two months of the last contact with the index case, tuberculin skin tests, QFT-2G tests and chest X-rays were undertaken. After 6 months, chest X-rays were taken, and after 9 months, QFT-2G tests and chest CT scans were also undertaken. The tuberculin skin tests after two months showed a bimodal distribution, and 10 were QFT-2G positive and 2 showed doubtful reaction. The latter 12 persons underwent chemoprophylaxis. After 6 months, however, out of 31 QFT-2G negative persons, 2 developed pulmonary tuberculosis. Moreover, after 9 months, chest CT scans revealed 5 pulmonary tuberculosis patients. Three out of 7 new patients showed positive or doubtful reactions in QFT-2G tests undertaken after 9 months. The sensitivity of QFT-2G tests is reported to be 80 to 90%, and the possibility of false negative is not negligible. We propose measures for public health center to conduct the contacts examination as follows; In case of high QFT-2G positive (including doubtful reaction) rate and/or a bimodal distribution of tuberculin skin test result, many infected persons are likely to be included in the group; and the following measures are recommended; 1) Necessity of chemoprophylaxis should be judged considering both tuberculin skin test results and the situation of contact with the index case, and not only by QFT-2G test results. 2) QFT-2G negative persons also need to be followed with chest X-rays.

[Primary isoniazid preventive therapy : A strategy still relevant in the era of test and treat ; literature review].

Tuberculosis remains a public health threat responsible as recently as 2018 for more than one million deaths. Chemoprophylaxis with isoniazid is one of the strategies implemented to control the disease. Although it is not yet widely prescribed, its utilization raises additional questions in the "test and treat" era of for anti-retroviral therapy. The objective of this study is to review the different randomized controlled trials of antitubercular Isoniazid Preventive Therapy (IPT). We have distinguished (a) "efficacy trials" (ET) comparing IPT to a placebo or the absence of chemoprophylaxis and (b) "IPT regimen trials" (RT) comparing IPT to one or several other regimens. Literature search (keywords from published articles found in the Medline and Scopus data bases: "tuberculosis", "prophylaxis", "HIV", "randomized controlled trial") and standardized reading of selected articles reporting results from randomized trials of IPT in HIV-infected people. Eighteen selected trials (11 ET and 7 RT), including 19,725 participants. The regimens studied were 3H, 6H, 9H, 12H, 12H, 36H/2RZ, 3RH, 3RZ, 3RHZ, and 3HP [H: Isoniazid, R: Rifampicin, Z: Pyrazinamide, P: Rifapentine]. Ten in Africa, three in Haiti, one in India, one in the USA, one in the Americas and two multi-continental trials. In ET with or without antiretrovirals (ART), IPT significantly reduces the risk of tuberculosis, by 32 to 71%. In ET prior to ART, IPT does not appear to reduce mortality. In ET in patients receiving ART, on the other hand, IPT reduces mortality. As regards RT, there seems to be no reason to prefer other regimens to IPT. Tolerance is good. Importantly, IPT may reduce (rather than worsen) the risk of multidrug-resistant bacilli selection by decreasing the number of TB episodes and, consequently, the number of curative tuberculosis treatments. Far from becoming obsolete due to ARV treatment, IPT has remained a timely and relevant intervention.

[Estimation of the possibilities of using unified chemotherapy regimens in new cases of pulmonary tuberculosis in old-age children and adolescents].

A hundred and forty children aged 13 to 17 who had new-onset active pulmonary tuberculosis were examined. There was a predominance of infiltrative tuberculosis (63.6%) in the pattern of its clinical forms. The processes were more frequently disseminated (79.3%) with lung tissue decay in every two patients (55.1%) and bacterial discharge in every three patients (39.3%). Among the new cases of pulmonary tuberculosis, the proportion of its multidrug resistance was 7.9%. The routine regimens were used for treatment. The efficiency of intensive-phase (IF) treatment was evaluated in 85 patients, including 18 patients receiving chemotherapy (CT) (HRZ/E/S) regimen 3 (Group 1), 45 having CT (HRZ/E/S) regimen 1 (Group 2), and 22 having CT (HRZE[A][Fq]/[Pt]) regimen 2B (Group 3). Clinical laboratory, Xray, and microbiological findings were criteria for evaluating the efficiency of IP CT. Abacillation occurred in all cases by month 4 of therapy. By and large, the efficiency of IF CT was 90.6% in new cases of pulmonary tuberculosis among old-age children and adolescents. In patients with disseminated processes, it ranged from 81.8% (Group 3) to 91.1% (Group 2) depending on the extent of lung tissue damage. The efficiency of therapy was as high as 100% in patients with circumscribed processes. Polyresistant resistance of Mycobacterium tuberculosis (MBT) to chemical agents, including multidrug resistance (7.9%), was a main reason of ineffective IF treatment (9.4%) in new cases of pulmonary tuberculosis among old-age children and adolescents. Overall, the actual use rate of routine CT regimens was 65.9% in new cases of pulmonary tuberculosis and adolescents. Uncontrolled adverse reactions to antituberculous drugs and drug resistance in MBT were reasons for deviations of routine regimens (modifications, use of individual regimes).

Low uptake of isoniazid window prophylaxis in patients exposed to a health-care worker with pulmonary tuberculosis in a paediatric ward.

A nurse on a paediatric multidisciplinary ward was diagnosed with smear-positive pulmonary tuberculosis. Children <2 years old, immunocompromised, or >40 h of contact (n = 173) were contact-traced. Children received clinical review, chest X-ray, tuberculin skin test (TST; <5 years old) and/or an interferon-gamma release assay (Quantiferon TB-Gold, ≥5 years old). Infants <6 months old or children <5 years old screened <2 months from exposure were recommended isoniazid window prophylaxis (WP) until a repeat TST at 6 months old or 8-10 weeks after the last exposure to the index case, respectively. Empiric treatment for latent tuberculosis infection (LTBI) was individually considered for immunocompromised patients. Of 173 children (135 immunocompetent, 38 immunocompromised), two were uncontactable, seven refused screening and two immunocompromised children excluded. Eight of 126 immunocompetent children were diagnosed with LTBI (initial TST positive n = 7, TST conversion n = 1); seven started isoniazid. Thirty-two of 36 immunocompetent children were recommended WP; 15 accepted (one non-compliant after 1 month). Six of seven immunocompromised children accepted empiric LTBI treatment due to severe immunosuppression/initial indeterminate Quantiferon TB-Gold result. Of 15 immunocompromised children offered WP, only five accepted. There was high acceptance of screening but low uptake of isoniazid WP in high-risk children exposed to pulmonary tuberculosis. Perception of exposure risk and chemoprophylaxis should be explored further.

A community-based isoniazid preventive therapy for the prevention of childhood tuberculosis in Ethiopia.

Although children in contact with adults with tuberculosis (TB) should receive isoniazid (INH) preventive therapy (IPT), this is rarely implemented. To assess whether a community-based approach to provide IPT at the household level improves uptake and adherence in Ethiopia. Contacts of adults with smear-positive pulmonary TB (PTB+) were visited at home and examined by health extension workers (HEWs). Asymptomatic children aged <5 years were offered IPT and followed monthly. Of 6161 PTB+ cases identified by HEWs in the community, 5345 (87%) were visited, identifying 24 267 contacts, 7226 (29.8%) of whom were children aged <15 years and 3102 (12.7%) were aged <5 years; 2949 contacts had symptoms of TB and 1336 submitted sputum for examination. Ninety-two (6.9%) were PTB+ and 169 had TB all forms. Of 3027 asymptomatic children, only 1761 were offered (and accepted) IPT due to INH shortage. Of these, 1615 (91.7%) completed the 6-month course. The most frequent reason for discontinuing IPT was INH shortage. Contact tracing contributed to the detection of additional TB cases and provision of IPT in young children. IPT delivery in the community alongside community-based TB interventions resulted in better acceptance and improved treatment outcome.

Development of interstitial pneumonia in a patient with rheumatoid arthritis induced by isoniazid for tuberculosis chemoprophylaxis.

Here, we report a 56-year-old patient with rheumatoid arthritis (RA) who had been treated with methotrexate and sulfuasalazine, but the disease activity remained high. Therefore, we planned TNF-blocker treatment for this patient. A tuberculin skin test was positive, we started anti-tuberculosis (TB) chemoprophylaxis with isoniazid (INH). However, liver dysfunction was appeared after 2 weeks from the start of INH. Therefore, we discontinued INH transiently and tried the desensitization of INH. However, interstitial pneumonia was developed 2 weeks after the re-start of INH, we decided to stop the INH prophylaxis. Interstitial pneumonia was improved by corticosteroid treatments. This case report shows that INH-induced IP can be occurred during the course of anti-TB chemoprophylaxis in patients with RA.

Pediatrics_Nelson

Infants, children, and adolescents exposed to adults in high-risk categories 10 mm of induration is a positive test. For HIV-positive patients,those with recent tuberculosis contacts, patients with evidenceof old healed tuberculosis on chest film, or immunosuppressedpatients, 5 mm is a positive test (see Chapter 124). The CDC hasapproved (in adults) the QuantiFERON-TB Gold Test, whichhas the advantage of needing one office visit only.

[Preventive therapy in middle-aged and elderly persons selected from the population-based screening by mass miniature radiography--methodological aspect and adverse reactions].

The notification rate of tuberculosis in Japan was 31.0 per 100,000 in 2000. The rate was especially high among the elderly population, reaching 85.5 per 100,000 among those over 65 years of age. We conducted a study of preventive therapy in middle-aged and elderly persons selected from the population-based screening by the mass miniature radiography. The eligible criteria were 50-79 years of age, fibrous lesion which were compatible with healed tuberculosis and showed no change for at least one year, no previous treatment for tuberculosis, normal liver function tests, and no serious disease at the time of study. The eligible criteria for liver function tests in this study was less than 50 IU/L of AST and ALT value, and less than 1.5 mg/dl of T-bil level. A total of 13,219 people underwent TB screening in 4 cities in 1997 and 2 cities in 1998. Among them, 440 persons fulfilled the above criteria based on the screening records and chest X-ray films. The municipal offices sent letters to 418 people, except 22 whose addresses were unknown, to obtain permission to use their addresses and results of screening in our study. Permission was obtained from 137 persons and we sent them invitation letters for cost-free physical checkup service. Ninety-five persons visited us, and we offered them physical checkup and explained about our study. After obtaining the informed consent, we performed chest X-ray and sputum examination for 3 consecutive days. Finally 29 people were enrolled in the study. They were divided into 4 groups by sex and age, and were randomly assigned to one of two treatment groups. One group took 300 mg of INH per day for 6 months and the other group was only followed up by chest X-ray. Fourteen out of 29 persons began to take INH and received monthly liver function test. All the subjects were scheduled to follow by medical checkup every 6 months for 5 years. The proportion of taking INH tablets was estimated to range from 94% to 100%, based on the calendar for record of taking medication and the number of remaining tablets each month. Six (42.9%) of 14 persons reported adverse reactions. Two of 6 persons complained some of diarrhea, vomiting and gastrointestinal disturbance within 2 weeks, and discontinued taking INH, although none of them showed abnormal liver function tests. Two of 6 persons who reported some kinds of symptoms and 2 of 8 persons who did not complain of any symptoms showed abnormal liver function tests. The abnormal liver function tests had developed from 2 months after the beginning of INH taking in most of the persons and the abnormality improved after the completion of 6-month treatment. We have followed them for a maximum duration of 2.5 years, and 3 cases dropped out from the study. These defaulted cases had completed 6 months of INH. One person (69 y.o. male) was diagnosed as active TB by his chest X-ray film at the 6th month medical checkup, although it was not confirmed bacteriologically. One person (62 y.o. female) had the mastectomy for breast cancer 7 months before the entry to this study and relapsed at the 8th month after the entry. One person (73 y.o. female) was diagnosed as lung cancer at the medical checkup on 2.5 years. Besides them, 4 persons were suspected of worsening the abnormal shadows on chest X-ray films; one was from the INH group and three were from the follow-up group. However none of them was diagnosed clinically and bacteriologically as active tuberculosis.


Vasoactive intestinal peptide (VIP). VIPoma-diarrhea. The 3.

A 40-year-old woman, with no personal or family history of interest, presents several days of watery diarrhea, very abundant, accompanied by loss of 10 kg of weight, flushing and facial reddening, together with lipothymias and colicky abdominal pain, with hypokalemia in the laboratory data. An abdominal ultrasound shows a mass of 1.5 cm in diameter in the pancreatic tail. Among the following, your primary diagnostic suspicion is:

[Use of a somatostatin analog to improve a patient's condition and the subsequent diagnosis of pancreatic VIPoma:a case report].

A 68-year-old woman with an 11-day history of sudden abdominal pain and severe watery diarrhea was transferred to our hospital due to an exacerbation of renal function despite hydration. After treatment for dehydration and acidemia was provided in our intensive care unit, patient's renal function improved. Contrast-enhanced abdominal computed tomography was finally performed, revealing a hypervascular pancreatic mass with multiple hepatic masses. This imaging finding along with her clinical symptoms indicated watery diarrhea hypokalemia achlorhydria (WDHA) syndrome caused by a pancreatic VIPoma. Somatostatin analog was administered immediately leading to the improvement of her diarrhea and her general condition. As a result, endoscopic ultrasonography-guided fine-needle aspiration could be performed. Consequently, she was diagnosed with a pancreatic neuroendocrine tumor. She then underwent surgical resection of the pancreatic tumor and liver metastasis. As revealed in the immunohistochemical analysis of the excised tumor tissue, VIP was highly expressed, resulting in the final diagnosis of pancreatic VIPoma. Therefore, the immediate use of a somatostatin analog is crucial for improving the patient's general condition and achieving a definitive diagnosis pathologically when a patient is suspected of having a pancreatic VIPoma.

Pancreatic neuroendocrine tumor

Functional tumors are often classified by the hormone most strongly secreted, for example: gastrinoma: the excessive gastrin causes Zollinger–Ellison syndrome (ZES) with peptic ulcers and diarrhea insulinoma: hypoglycemia occurs with concurrent elevations of insulin, proinsulin and C peptide glucagonoma: the symptoms are not all due to glucagon elevations, and include a rash, sore mouth, altered bowel habits, venous thrombosis, and high blood glucose levels VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound chronic watery diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA or pancreatic cholera syndrome) somatostatinoma: these rare tumors are associated with elevated blood glucose levels, achlorhydria, cholelithiasis, and diarrhea less common types include ACTHoma, CRHoma, calcitoninoma, GHRHoma, GRFoma, and parathyroid hormone–related peptide tumor

Diagnosis of non-Zollinger-Ellison syndrome, non-carcinoid syndrome, enteropancreatic neuroendocrine tumours.

The diagnosis of entero-neuropancreatic tumours different from Zollinger-Ellison syndrome and carcinoid syndrome require an high index of suspicion and even when they are associated to virulent syndromes such as VIPoma or insulinoma syndrome the mean delay in diagnosis is of 4 years. Symptomatic hypoglycaemia due to inappropriate insulin release from insulinoma and watery diarrhoea leading to dehydration caused by elevated circulant vaso-intestinal peptide levels are present in the 90% and 100% of the patients at presentation of the respective syndrome. Somatostatinoma syndrome has a far more subtle presentation and it tends to present much later during the disease course. The diagnosis is based on the presence of gallstones, diabetes, weight loss, diarrhoea and steatorrhoea. Growth hormone releasing factor neuroendocrine tumours (GRFoma) present with acromegaly and account for less than 2% of the acromegalic patients in which the growth hormone is from an ectopic source located in the pancreas. The Cushing's syndrome diagnosis due to rare ectopic neuroendocrine tumour adrenocorticotropic hormone secretion can be made only with selective angiography, whereas non-functional and pancreatic polypeptide producing neuroendocrine tumours (PPoma) present without any symptoms. Finally, multiple endocrine neoplasia type one occurs more commonly with somatostatinoma or GRFoma, conversely patients with multiple endocrine neoplasia type one can develop insulinoma (20%) or PPoma (60%).

[An unusual case of multiple endocrine neoplasia].

The patient A.M., woman, presented Multiple Endocrine Neoplasia, associating hyperparathyroidism, an adrenal tumor and pancreatic tumor; one can observe that the disease had features of Multiple Endocrine Neoplasia type-1 (pancreatic tumor), as well as Multiple Endocrine Neoplasia type-2 (MEN-2, pheochromocytoma), while the hyperparathyroidism is common for both two types of the syndrome. The development of the disease is extended over approximate forty years of life and finally led to death. The first symptoms appeared during pregnancy, at age 26, when the severe hyperparathyroidism determined bone mass acute loose, with decrease in height by affecting columnary vertebrae, severe bone pain due to bone resorption and soon after symptoms of renal stone disease. The patient suffered two surgical interventions for renal lithiasis. The biliary symptoms required also the surgical removal of the gall bladder, putting the diagnosis of active metabolic stone disease. At age 56, was established the diagnosis of carcinoma of the adrenal cortex, which was solved with surgical therapy. At age 66, digestive symptoms suggested the presence of a carcinoid tumor. Abdominal ultrasonography revealed a well-lined pancreatic tumor of 2-3 centimeters in diameter, probably adenoma. The malignant evolution of this tumor was rapid, leading to death in less than two years. The constant refuse of other investigations, by the patient, made us incapable to determine the type of secretion of the pancreatic tumor; we rather suspected a VIPoma, because of the watery diarrhea and severe weight loss. The most difficult to treat was anyway the hyperparathyroidism and its complications.

A clinical analysis on functioning pancreatic neuroendocrine tumors (focusing on VIPomas): a single-center experience.

VIPomas are generally rare functioning pancreatic neuroendocrine tumors (PanNETs) that cause watery diarrhea, hypokalemia, and achlorhydria. Due to their extreme rarity, the clinicopathological features and outcomes of VIPomas have not been well reported. This study aimed to determine the diagnostic and therapeutic characteristics and prognosis of VIPomas and to compare them with other PanNETs at a Japanese reference hospital. Medical records of 293 patients with PanNETs were collected. Patient and tumor characteristics and outcomes were retrospectively reviewed. This cohort had only 1.4% (four patients) of patients with VIPomas, and three of these patients changed from non-functioning (NF-) PanNETs during their disease course. Recurrences of hormonal symptoms were observed in all patients despite the initial controls, and all of them died from their disease, more specifically mainly from hormonal symptoms. Compared to the other PanNETs, VIPomas were all located at the pancreatic tail, were larger, and had a higher Ki-67 index and more metastasis. The median survival time was significantly shorter for patients with VIPoma than for those with NF-PanNET (5.9 vs. 26.7 years, p < 0.0001), insulinoma (21.8 years, p < 0.0001), and gastrinoma (12.3 years, p = 0.0325). This study presents the possibility of shifting from non-symptomatic to symptomatic VIPomas as they grow or of transforming from NF-PanNETs to VIPomas. VIPomas should be considered in patients with relatively large NF-PanNETs, especially those located in the pancreatic tail, when diarrhea is continuously observed. As hormonal symptoms are an important cause of death in VIPomas, long-term symptomatic control, which is relatively difficult, is of great significance.

APUDoma -- History and Physical -- Pancreatic NETs

Pancreatic NETs cause different variable clinical syndromes depending on the type of hormones secreted. For example, beta-cell neoplasm or insulinoma, the most common GI NETs, secretes excess insulin causing hypoglycemia, with the relief of symptoms after glucose administration (Whipple triad) and hypokalemia. Zollinger-Ellison syndrome is caused by gastrinoma secreting gastrin hormone characterized by multiple peptic ulcers in atypical sites such as the duodenum and jejunum, typically resistant to proton pump inhibitors, diarrhea, and abdominal pain. Glucagonomas produce excess glucagon hormone, typically cause diabetes, dermatitis (necrolytic migratory erythema), deep vein thrombosis, and depression. VIPoma produces excess vasoactive intestinal peptide associated with voluminous watery diarrhea (10–15 L/day) and flushing. [13]

Successful Treatment of Hypokalemic Rhabdomyolysis Caused by a Pancreatic VIPoma: A Case Report.

BACKGROUND VIPomas are rare neuroendocrine tumors typically located in the pancreas. The majority of cases autonomously secret vasoactive intestinal polypeptide (VIP), which can result in profuse, refractory, watery diarrhea. The fluid and electrolyte imbalance can progress to dehydration and profound hypokalemia, resulting in the watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome. One previous case of a pancreatic VIPoma progressing to hypokalemic rhabdomyolysis has been described. CASE REPORT A 33-year-old woman presented with 3 months of progressive, refractory diarrhea and weakness. Her serum VIP level was elevated and imaging discovered a mass in the region of the pancreatic tail. Laparoscopic partial pancreatic resection was performed and a 3.7-cm diameter, solitary stage T2 N0 M0, well-differentiated carcinoma was removed. CONCLUSIONS A high index of suspicion is important when diagnosing chronic diarrhea. Minimally invasive surgery is an option in the surgical treatment of pancreatic VIPoma.

VIPoma

Symptoms and signs The major clinical features are prolonged watery diarrhea (fasting stool volume > 750 to 1000 mL/day) and symptoms of hypokalemia and dehydration. Half of the patients have relatively constant diarrhea while the rest have alternating periods of severe and moderate diarrhea. One third have diarrhea < 1yr before diagnosis, but in 25%, diarrhea is present for 5 yr or more before diagnosis. Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent symptoms. Hypokalemia and impaired glucose tolerance occur in < 50% of patients. Achlorhydria is also a feature. During attacks of diarrhea, flushing similar to the carcinoid syndrome occur rarely. Diagnosis Besides the clinical picture, fasting VIP plasma level may confirm the diagnosis, and CT scan and somatostatin receptor scintigraphy are used to localise the tumor, which is usually metastatic at presentation.

[Vipoma of the pancreas. Apropos of a case and review of the literature].

Pancreatic endocrine tumors are uncommon; of this type of tumors, the Verner-Morrison's syndrome, WDHA or vipoma is diagnosed very rarely. The present paper is a report of a pancreatic vipoma in a 60 year-old female; she presented with watery diarrhea, facial flushing, hypokalemia, hypochlorhydria, metabolic acidosis and reversible renal failure; these are the usual manifestations of the syndrome. The diagnosis was made on the basis of radiological imaging, CAT and arteriography as well as the finding or elevated levels of vasoactive intestinal peptide (VIP). The surgical resection of the tumor was followed by the remission of the symptoms and normalization of the plasmatic levels of VIP. It is necessary to recognize this type of tumors because the only way to achieve a curative surgical resection is after an early diagnosis.

VIPoma

A VIPoma or vipoma () is a rare endocrine tumor that overproduces vasoactive intestinal peptide (thus VIP + -oma). The incidence is about 1 per 10,000,000 per year. VIPomas usually (about 90%) originate from the non-β islet cells of the pancreas. They are sometimes associated with multiple endocrine neoplasia type 1. Roughly 50–75% of VIPomas are malignant, but even when they are benign, they are problematic because they tend to cause a specific syndrome: the massive amounts of VIP cause a syndrome of profound and chronic watery diarrhea and resultant dehydration, hypokalemia, achlorhydria, acidosis, flushing and hypotension (from vasodilation), hypercalcemia, and hyperglycemia. This syndrome is called Verner–Morrison syndrome (VMS), WDHA syndrome (from watery diarrhea–hypokalemia–achlorhydria), or pancreatic cholera syndrome (PCS). The eponym reflects the physicians who first described the syndrome.

VIPomas: an update in diagnosis and management in a series of 11 patients.

VIPoma is a rare pancreatic endocrine tumor (PET) which secretes excessive amounts of VIP (Vasoactive Intestinal Peptide) that causes a special clinical syndrome characterized by secretory diarrhea, hypokalemia and achlorhydria. Among a total number of 76 patients (pts) with PETs, we present in this study 11 pts with VIPoma syndrome focusing on our diagnostic and therapeutic approach, in parallel with a brief review of the literature. Eleven pts (7 males and 4 females), aged from 2 to 83 years (mean age 53.1 years) were included. The diagnosis was based upon compatible clinical features and serum VIP values and was supported by the estimation of other peptides and neuroendocrine markers such as gastrin, pancreatic polypeptide and chromogranin-A (CgA). In 10/11 pts, diagnosis was confirmed histopathologically. The primary or metastatic lesions were located by conventional imaging methods or by OCTREOSCAN or Endoscopic Ultrasound (EUS). The follow-up period ranged from 2.5-13.5 years (mean 4.8 years). Chronic secretory diarrhea, which persisted despite fasting, was the main symptom in all pts of our study. VIP levels at the time of diagnosis were more than 3 or 10 times the upper normal limit in 7/11 (63.6%) or 4/11 (36.4%) pts, respectively. The primary lesion was detected by CT scan or MRI in 6/11 (54.5%), with EUS or abdominal angiography in 4/11 (36.4%). OCTREOSCAN revealed a solitary lesion in the right hepatic lobe, not detected by all the previous studies, while it detected, as a whole, the primary lesion in 10/11 (91%), and the metastases in 3/4 (75%) pts. In 7/11 (63.6%) the primary lesion was located in the pancreas, whereas in the rest it was in the duodenum or retroperitoneum. A surgical resection was possible in 7/11 (63.6%) pts, while pts with metastatic disease already or poorly differentiated tumors also received additional treatment with somatostatin analogues and chemotherapy. Liver metastases and poor differentiation of tumors seemed to be negative prognostic factors. Clinical suspicion, early diagnosis and precise management may affect survival and improve the quality of life of patients. Also, surgical treatment, as extensive as possible, in combination with somatostatin analogues or chemotherapy when necessary, may also result in prolonged survival, also in patients with advanced disease.

Sporadic pancreatic vasoactive intestinal peptide-producing tumor (VIPoma) in a 47-year-old male.

VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six-month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1×3.3×4.7cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7×6.1×6.8cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71pg/mL) and normalized electrolyte and acid-base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18months. We also present a brief literature review on VIPoma.

Pancreatic VIPoma as a Differential Diagnosis in Chronic Pediatric Diarrhea: A Case Report and Review of the Literature.

Chronic diarrhea is a common chief complaint in the pediatric population with a wide range of diagnostic differentials; as such, whilst suspecting common causes, less prevalent conditions tend to be overlooked, such as neuroendocrine tumor pathologies. VIPomas are characterized by hypersecretion of the vasoactive intestinal peptide (VIP), causing watery diarrhea, hypokalemia, and achlorhydria. Nonetheless, its low incidence rate in children makes it an easily unnoticed pathology. Herein, we report a case of a 14-year-old female patient and a review of relevant literature. The patient complained of 7-month history of watery diarrhea, multiple emetic episodes, and relevant past medical history of multiple hospitalizations. Chronic diarrheal disease work-up studies, including a high VIP scintigram, showed a lesion suggestive of a VIPoma-type neuroendocrine pancreatic tumor. A distal pancreatectomy was performed with a complete resolution of the symptoms. When faced with a pediatric patient presenting with chronic secretory diarrhea and whose work-up studies rule out the most common pathologies, the possible presence of a neuroendocrine tumor as VIPoma should be considered.

Ventricular fibrillation resulting from electrolyte imbalance reveals vipoma in MEN1 syndrome.

Sporadic VIPoma is an exceedingly rare tumor with an annual incidence of 1:10 million people worldwide, yet it is described in approximately 5 % of MEN1 patients. The majority of VIPomas are malignant and radical surgery is the best therapeutic option. A 58-year-old man presented with cardiocirculatory arrest due to ventricular fibrillation. The patient had a 3-month history of epigastric pain with diarrhea. After reanimation, laboratory data revealed severe hypokalemia and hypercalcemia. Further investigations showed hyperparathyroidism, left adrenal adenoma and pituitary microprolactinoma and genetic diagnosis of MEN1 syndrome was made. Abdominal computed tomography revealed a 45 × 30 mm mass of the pancreatic head and two hepatic lesions, which proved to be neuroendocrine after 68 Ga PET and needle biopsy. Vasoactive intestinal peptide (VIP) serum level had increased. Subsequently the patient underwent pylorus-preserving pancreaticoduodenectomy and hepatic resection. Intraoperative VIP returned to normal values. Histopathology confirmed a pancreatic VIPoma metastatic to the liver. The postoperative course was unremarkable and the patient is well with no evidence of disease at a 48 months follow-up. Even in case of anusual presentation, when two or more main clinical findings of MEN1 related tumors are present, unrespectively to the presence of MEN1 mutation, MEN1 syndrome should be suspected. Surgery in MEN1 pancreatic neuroendocrine tumors is indicated both to treat symptoms and to avoid oncological progression even in advanced cases.

Vasoactive Intestinal Peptide Tumor as the Cause of Persistent Diarrhea: A Diagnostic Challenge.

Although chronic diarrhea is frequent, some of its causes are rare, namely, neuroendocrine tumors (NETs). Due to their rarity and non-specific symptoms, such as diarrhea, they are often underdiagnosed. An 80-year-old woman presented to the emergency department due to emesis and watery diarrhea. Blood tests showed acute kidney injury, hypokalemia, and metabolic acidosis. An abdominal computed tomography revealed a 51 mm pancreatic lesion. An endoscopic ultrasound-guided biopsy raised the hypothesis of a NET. The patient refused surgery and was lost to follow-up. At the eighth hospitalization, 11 months later, the suspicion of a vasoactive intestinal peptide tumor (VIPoma) was raised and confirmed by assessing the vasoactive intestinal peptide (VIP) levels (>100 pmol/L). Octreotide was started with the resolution of the symptoms. 68Ga-DOTANOC positron emission tomography/computed tomography excluded metastatic disease. After six months of octreotide therapy, the tumor shrunk 13 mm in maximum diameter. At the last follow-up, one year later, she remained asymptomatic. The delayed diagnosis of VIPoma led to multiple life-threatening episodes. This case highlights the importance of considering all potential differential diagnoses of common symptoms such as diarrhea. Although VIPomas are rare, clinicians should be aware of this entity and suspect this diagnosis in patients with chronic diarrhea with a poor response to standard antidiarrheal agents. Somatostatin analogs should be promptly prescribed for symptom control and tumor progression prevention in patients who refuse surgery or have unresectable tumors. Tumor shrinkage might also be observed in these cases.

Giant metastatic VIPoma in the liver.

A case of giant metastatic liver VIPoma manifesting WDHA syndrome is described. The patient was a 33-year-old Japanese male who was admitted because of persisting watery diarrhea and weight loss. Laboratory examinations revealed marked hypokalemia, mild hypercalcemia and highly elevated plasma vasoactive intestinal peptide (VIP) and glucagon levels. Intensive imaging examinations disclosed two large tumors in the liver but not in other organs, including the pancreas. Laparoscopy disclosed a slightly elevated purplish-colored large tumor on the surface of the apparently normal liver. At operation, however, a small hard nodule was observed in the tail of the pancreas. Histologically, it was revealed to be a VIPoma resembling a carcinoid or an islet cell tumor, and was identical to the liver tumors. Thus, this neoplasm was considered to be a VIPoma of pancreatic origin, with metastatic lesions in the liver.

Pancreatic VIPomas: subject review and one institutional experience.

VIPomas are rare pancreatic endocrine tumors associated with a well-defined clinical syndrome characterized by watery diarrhea, hypokalemia, and metabolic acidosis. The objective of this study was to review a single institution's experience with VIPomas, as well as to review the English literature. A retrospective review of the Johns Hopkins pancreatic database revealed four cases of VIPoma, with three patients being male. All patients presented with watery diarrhea, hypokalemia, hypercalcemia, and acidosis. All patients had no family history of multiple endocrine neoplasia. Computed tomography revealed the primary pancreatic tumor in all patients, with three tumors located in the tail of the pancreas. One tumor involved the entire pancreas. Computed tomography and/or octreotide radionuclide scans identified hepatic metastasis in three patients. Mean serum vasoactive intestinal polypeptide levels were 683 pg/ml (range 293 to 1,500 pg/ml). All patients underwent resection of the pancreatic primary tumor. Two patients also had simultaneous liver resections. All patients had evidence of malignancy as defined by the presence of metastatic lymph nodes and/or hepatic metastases. Two patients had complete resolution of symptoms after surgical resection. One patient required radioablation of liver metastases and adjuvant octreotide therapy for control of symptoms. One patient died of progressive metastatic disease 96 months after surgery, whereas the other three remain alive. Extended, meaningful survival can be achieved for VIPoma patients, combining an aggressive surgical approach with additional strategies for treatment of unresected disease.

Pancreatic Islet Cell Cancer -- History and Physical

Insulinoma presents with hyperinsulinemic hypoglycemia in patients. The disease is manifested as the Whipple triad. This includes symptoms of low blood glucose, along with the symptoms of hypoglycemia. Moreover, the symptoms should settle with glucose intake. [9] VIPoma in a patient can cause watery diarrhea, hypokalemia, and achlorhydria. This is called VIPoma syndrome or WDHA syndrome. [10]

Physiology, Gastrin -- Pathophysiology

A normal fasting serum gastrin level virtually excludes ZES. 70% to 75% of gastrinomas are sporadic; however, 25% to 30% of these tumors are associated with type 1 multiple endocrine neoplasia (MEN1). [20] In patients with multiple endocrine neoplasia type I (MEN1), an autosomal-dominant disorder, there is a clustering of the pituitary, parathyroid, and pancreatic tumors. Patients diagnosed with gastrinoma must be evaluated for MEN1 symptoms by asking about family history, hyperparathyroidism symptoms (hypercalcemia, nephrolithiasis), or symptoms of pituitary tumors (most commonly a prolactinoma, which causes galactorrhea in females while causing headache and bitemporal hemianopia in males). Labs are necessary to measure serum calcium, parathyroid hormone, and prolactin. [21] Instead of gastrinoma, they can also present with insulinoma (symptoms of hypoglycemia), glucagonomas (necrotizing migratory erythema (NME), diabetes, weight loss, anemia), or VIPoma (watery diarrhea, hypokalemia, hypochlorhydria). [22] Multiple imaging modalities are available to delineate the tumor, including CT, MRI, and somatostatin-receptor scintigraphy. Patients diagnosed with gastrinoma must be evaluated for MEN1 regarding family history, history of hypercalcemia, nephrolithiasis, or pituitary tumors, and labs are necessary to measure serum calcium, parathyroid hormone, and prolactin.

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Endocrine Tumors of the Gastrointestinal Tract and Pancreas Abbreviations: ACTH, adrenocorticotropic hormone; GRFoma, growth hormone–releasing factor secreting pancreatic endocrine tumor; IGF-II, insulin-like growth factor II; MEN, multiple endocrine neoplasia; pNET, pancreatic neuroendocrine tumor; PPoma, tumor secreting pancreatic polypeptide; PTHrP, parathyroid hormone–related peptide; VIPoma, tumor secreting vasoactive intestinal peptide; WDHA, watery diarrhea, hypokalemia, and achlorhydria syndrome. aPancreatic polypeptide–secreting tumors (PPomas) are listed in two places because most authorities classify these as not associated with a specific hormonal syndrome (nonfunctional); however, rare cases of watery diarrhea proposed to be due to PPomas have been reported. Because a large proportion of nonfunctional pNETs (60–90%) secrete PP, these tumors are often referred to as PPomas (Table 113-2).

Surgery_Schwartz

have the worst prognosis.Vasoactive Intestinal Peptide-Secreting TumorIn 1958, Verner and Morrison first described the syndrome associated with a pancreatic neoplasm secreting VIP. The clas-sic clinical syndrome associated with this pancreatic endocrine neoplasm consists of severe intermittent watery diarrhea leading to dehydration, and weakness from fluid and electrolyte losses. Large amounts of potassium are lost in the stool. The vasoac-tive intestinal peptide-secreting tumor (VIPoma) syndrome is also called WDHA syndrome due to the presence of watery diarrhea, hypokalemia, and achlorhydria. The massive (5 L/d) and episodic nature of the diarrhea associated with the appropriate electrolyte abnormalities should raise suspicion of the diagnosis. Serum VIP levels must be measured on multiple occasions because the excess secretion of VIP is episodic and single measurements might be normal and misleading. A CT scan localizes most VIPomas, although as with all islet cell tumors, EUS is

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clinical manifestation in 10%. While other secretagogues released with gastrin may play a role, the diarrhea most often results from fat maldigestion owing to pancreatic enzyme inactivation by low intraduodenal pH. The watery diarrhea hypokalemia achlorhydria syndrome, also called pancreatic cholera, is due to a non-β cell pancreatic adenoma, referred to as a VIPoma, that secretes VIP and a host of other peptide hormones including pancreatic polypeptide, secretin, gastrin, gastrin-inhibitory polypeptide (also called glucose-dependent insulinotropic peptide), neurotensin, calcitonin, and prostaglandins. The secretory diarrhea is often massive with stool volumes >3 L/d; daily volumes as high as 20 L have been reported. Life-threatening dehydration; neuromuscular dysfunction from associated hypokalemia, hypomagnesemia, or hypercalcemia; flushing; and hyperglycemia may accompany a VIPoma. Medullary carcinoma of the thyroid may present with watery diarrhea caused by calcitonin, other

Clinicopathological data and treatment modalities for pancreatic vipomas: a systematic review.

Vasoactive intestinal peptide (VIP) secreting tumor (VIPoma) constitutes a rare functional neuroendocrine tumor that most often originates from pancreatic islet cells and presents as a sporadic, solitary neoplasm of the pancreas. The purpose of this study was to systematically review the literature of pancreatic VIPomas and report clinicopathologic data and treatment modalities for this rare entity. A systematic literature search was performed. The reviewed clinical series and case reports were included if they reported surgical treatment and also analyzed oncological outcomes on individual patients. Data extraction was performed using a standard registry pro-forma. The search resulted in 53 case reports and 2 case series including 65 patients in total. Median age reported was 54 years. The predominant pancreatic location was the pancreatic tail. The most common clinical symptom was watery diarrhea. Serum VIP levels were remarkably elevated in all patients. Distal pancreatectomy with or without splenectomy was the most commonly applied surgical procedure. Overall survival associated with pancreatic VIPoma was 67.7%, recurrence rate 40.4% and relevant median disease-free interval was 16 months. VIPomas are functional tumors that secrete excessive amounts of VIP. Clinically, production of VIP causes refractory watery diarrhea, hypokalemia and achlorydria. As far as diagnosis is concerned, elevated VIP plasma levels are required. Moreover, the majority of VIPomas are malignant or have already metastasized on diagnosis. Despite recent research on the therapeutic strategies against pancreatic VIPoma, surgical resection appears as the only potentially curative approach.

Pancreatic neuroendocrine tumor

Signs and symptoms Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose. Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either locally or at a metastasis. About 40% of PanNETS have symptoms related to excessive secretion of hormones or active polypeptides and are accordingly labeled as "functional"; the symptoms reflect the type of hormone secreted, as discussed below. Up to 60% of PanNETs are nonsecretory or nonfunctional, in which there is no secretion, or the quantity or type of products, such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin, do not cause a clinical syndrome although blood levels may be elevated. In total, 85% of PanNETs have an elevated blood marker.

Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors.

Endocrine tumors of the parathyroid and pancreas are encountered either as sporadic type or as part of multiple endocrine neoplasia type 1 (MEN 1). A high frequency of the loss of heterozygosity (LOH) has been observed in tumors of the sporadic type in the locus of the MEN 1 gene, which has recently been cloned and designated the menin gene. It would be of great interest to determine whether somatic mutations in the menin gene are responsible for the sporadic endocrine tumors. For this purpose, we have investigated the menin gene mutations in 21 sporadic parathyroid adenomas, 2 parathyroid carcinomas, 4 sporadic insulinomas, and 1 malignant VIP (vasoactive intestinal polypeptide)oma with WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, using PCR-single strand conformation polymorphism analysis and DNA sequencing. In none of these cases did the patient have a family history or other possible association with MEN 1. We have discovered somatic point mutations in two parathyroid adenomas (A340T and A541T), in one insulinoma (T429K), and in the malignant VIPoma (W198X). In addition, we have found two polymorphisms (D418D and V367V) in two parathyroid carcinomas and two parathyroid adenomas. Of these mutations and polymorphisms, three (A340T, T429K, and V367V) are first reported here, in the present article. Our results indicate that somatic mutations of the menin gene are responsible for a proportion of the sporadic parathyroid adenomas and pancreatic islet cell tumors.

Cervical metastases of glucagonoma in a patient with multiple endocrine neoplasia type 1: report of a case.

Multiple endocrine neoplasia type 1 (MEN 1) is a syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, duodenum, and pituitary gland. We report a case of cervical metastases of glucagonoma with MEN 1. The patient was a 34-year-old woman admitted to our hospital with epigastric pain. Her medical history included two resections of prolactinoma and two upper GI hemorrhages secondary to duodenal ulcers. Computed tomography (CT) showed two hypervascular lesions in the tail of the pancreas and cervical ultrasound showed multiple hypoechogenic ovoid images in the neck. A cervical CT scan confirmed two 15-mm lymph nodes in the left cervical region and 111In-DOTATOC imaging showed focal abnormal somatostatin expression in the pancreatic tail and the cervical nodes. The patient had asymptomatic hypoglycemic episodes, with blood sugar levels as low as 30 mg/dl, which raised our suspicion of MEN 1 associated with pancreatic insulinoma. Thus, we performed a distal pancreatectomy with bilateral cervical dissection and parathyroid gland resection. Histopathological examination revealed 12 pancreatic tumors as well as metastases in four cervical lymph nodes. The resected parathyroid glands had normal structure, suggesting parathyroid hyperplasia. A follow-up CT scan, 18 months after surgery, showed new tumors in the head of the pancreas and in the duodenal wall. A pancreatoduodenectomy was performed and histopathological examination revealed nine nonfunctioning endocrine tumors in the pancreas, one tumor in the duodenal wall, and metastases in two peripancreatic lymph nodes. The patient recovered well and remains asymptomatic.

InternalMed_Harrison

Pancreatic tumors are frequently (70–92%) metastatic at presentation, whereas 30–69% of SI somatostatinomas have metastases. Surgery is the treatment of choice for those without widespread hepatic metastases. Symptoms in patients with the somatostatinoma syndrome are also improved by octreotide treatment. VIPomas are NETs that secrete excessive amounts of vasoactive intestinal peptide (VIP), which causes a distinct syndrome characterized by large-volume diarrhea, hypokalemia, and dehydration. This syndrome also is called Verner-Morrison syndrome, pancreatic cholera, and WDHA syndrome for watery diarrhea, hypokalemia, and achlorhydria, which some patients develop. The mean age of patients with this syndrome is 49 years; however, it can occur in children, and when it does, it is usually caused by a ganglioneuroma or ganglioneuroblastoma.

ViPoma -- Introduction

Vasoactive intestinal peptide tumors (VIPoma) are neuroendocrine tumors secreting vasoactive intestinal peptide (VIP) in an unregulated manner. Werner and Morrison first described them in 1958 as a pancreatic tumor resulting in watery diarrhea and hypokalemia [1] . In 1973, the team of Bloom, Polak, and Pearse confirmed that the mediator was VIP [2] . The VIPoma syndrome is also known as Verner-Morrison syndrome, watery diarrhea, hypokalemia, and hypochlorhydria or achlorhydria (WDHA) syndrome, and pancreatic cholera syndrome [3] . This review highlights the clinical presentation, diagnosis, and management.

Multiple endocrine neoplasia type 1

A severe secretory diarrhea can develop and cause fluid and electrolyte depletion with non–β-cell tumors. This complex, referred to as the watery diarrhea, hypokalemia and achlorhydria syndrome (VIPoma) has been ascribed to vasoactive intestinal polypeptide, although other intestinal hormones or secretagogues (including prostaglandins) may contribute. Hypersecretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH resulting in Cushing's syndrome, and hypersecretion of somatotropin–releasing hormone (causing acromegaly) sometimes occur in non–β-cell tumors. All of these are rare in MEN 1.Nonfunctioning pancreatic tumors also occur in patients with MEN 1 and may be the most common type of pancreatoduodenal tumor in MEN 1. The size of the nonfunctioning tumor correlates with risk of metastasis and death.

Pancreatic Neuroendocrine Tumor Secreting Vasoactive Intestinal Peptide and Dopamine With Pulmonary Emboli: A Case Report.

The vasoactive intestinal peptide-secreting neuroendocrine tumor (VIPoma) is a very rare pancreatic tumor. We report the first case of a patient with VIPoma that co-secreted dopamine and had pulmonary emboli. A 67-year-old woman presented with 2 months of watery diarrhea, severe generalized weakness,6.8 kg of weight loss, a facial rash, and hypokalemia. Colonoscopy did not reveal the cause of the chronic diarrhea. Initial biochemical testing showed markedly elevated serum vasoactive intestinal peptide (VIP) and pancreatic polypeptide. Computed tomography scan of the abdomen and pelvis revealed a 5.4-cm distal pancreatic mass. Octreoscan showed an intense uptake in the area of the pancreatic mass. Incidental pulmonary emboli were found and treated. Additional biochemical testing revealed a markedly elevated urinary dopamine level. The patient received preoperative α-blockade and octreotide. She underwent a successful laparoscopic distal pancreatectomy. Postoperative urinary dopamine and pancreatic polypeptide were within normal limits. Serum VIP decreased by half but remained elevated. Pathology confirmed a grade 1 pancreatic neuroendocrine tumor without lymph node metastasis. The patient's symptoms resolved and no longer required octreotide. Metastatic workup including computed tomography, F18-fluorodeoxglucose positron emission tomography, and Ga68-DOTATATE scans were negative during 4 years of follow-up. VIPoma is a rare subtype of pancreatic neuroendocrine tumor that can secrete dopamine and can be associated with thromboembolism.

Life-threating diarrhea and acute renal failure secondary to pancreatic VIPoma treated by surgery.

Pancreatic neuroendocrine tumors represent less than 5% of all pancreatic tumors. They are a heterogeneous group of neoplasms with a diverse behavior and prognosis. Pancreatic vasoactive intestinal polypeptide tumor (VIPoma) is an exceptional tumor within this group due to its low incidence. The presence of pancreatic VIPoma should be clinically suspected in all patients with watery diarrhea, particularly when accompanied by a loss of potassium and bicarbonate and a pancreatic mass on imaging. There are other pathologies with similar symptoms; therefore, a correct differential diagnosis with an adequate treatment is essential for its management. We present the case of a 46-year-old patient who developed a prerenal kidney failure secondary to severe watery diarrhea after a diagnosis of pancreatic VIPoma. Thus, a resection was performed as the patient was rapidly deteriorating and required an intervention.

Necrolytic migratory erythema and pancreatic glucagonoma.

Necrolytic migratory erythema is a rare paraneoplastic dermatosis that may be the first clinical manifestation of the glucagonoma syndrome, a disorder characterized by mucocutaneous rash, glucose intolerance, hypoaminoacidemia, hyperglucagonaemia and pancreatic glucagonoma. The clinical case of a 45-year-old woman is presented. She had been experiencing weight loss, polydipsia, polyphagia, postprandial emesis, excessive hair loss and abdominal pain for two months. Erythematous, scaly and migratory plaques with 20 days of evolution were found on her trunk, perineum, elbows, hands, feet, inframammary and antecubital folds. The skin biopsy revealed noticeable vacuolar changes in high epidermal cells, extensive necrosis and thin orthokeratotic cornified layer. These findings pointed to a diagnosis of necrolytic migratory erythema. A suggestion was made to investigate a pancreatic glucagonoma. Laboratory tests showed moderate anemia, hyperglycemia and marked hyperglucagonaemia. Abdominal ultrasound revealed a mass in the tail of the pancreas measuring 6 x 5 x 5 cm which was resected. The histopathological findings were compatible with a diagnosis of glucagonoma, as confirmed by immunohistochemistry. Skin symptoms disappeared 10 days after the tumor resection. We can conclude that the histological changes defined may be clues that can lead the search for a distant skin disease and allow for its diagnosis. The histological pattern of vacuolation and epidermal necrosis should arouse suspicion of pancreatic glucagonoma.