Litiumassocierad hyperparatyreoidism: randomiserad studie för utvärdering av paratyreoidektomi hos litiumbehandlade patienter.
Litiumassocierad hyperparatyreoidism: randomiserad studie för utvärdering av paratyreoidektomi hos litiumbehandlade patienter.
Project number : 181871
Created by: Adrian Meehan, 2015-08-30
Last revised by: Adrian Meehan, 2018-03-29
Project created in: FoU Region Örebro län

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2014-09-01
Rekrytering/datainsamling pågår

Titel och sammanfattning

Populärvetenskaplig sammanfattning

Sedan John Cade upptäckte att litium var effektiv i behandlingen av manier, kvarstår litium som det effektivaste medlet för bipolär sjukdom.Trots ett stort antal studier som bekräftar Garfinkels ursprungliga iakttagelser om att litium kan orsaka hyperparatyreoidism (HPT), tycks sambandet fortfarande kontroversiellt. Litium tros påverka kalcium-känsliga receptorn (CSR). Det är okänt om påbörjad litiumbehandling demaskerar en redan patologisk bisköldkörtel eller orsakar patologiska förändringar i bisköldkörtlarna. Kalciumjonen är av stor betydelse för en lång rad fysiologiska processer och är mycket noggrant kontrollerad.
Hyperparatyreoidism är en vanlig sjukdom med en incidens på 1‰, något vanligare hos postmenopausala kvinnor. Kirurgi kvarstår som den rekommenderade förstahandsbehandling. Kunskapen om HPT associerad med litiumbehandling (LHPT) är bristfällig. Bipolär sjukdom uppskattas förekomma i 1-2%. LHPT förekommer hos 18% av litiumbehandlade patienter. Idag behandlas mer än 15.000 svenskar med litium. Vi vet fortfarande inte vilka effekter LHPT har på patientens symtomatologi. Knappt 300 fall av LHPT finns rapporterat i litteraturen, med avsevärda variationer i resultat och patologiska fynd. Den klart största studien talar för att konventionell kirurgi har dåliga långtidsresultat. Vår primära avsikt är att försöka kartlägga kroppslig och psykisk symtomatologi hos patienter med LHPT samt värdera huruvida kirurgisk behandling påverkar dessa symtom på ett positivt sätt.

Sammanfattning på engelska

Since John Cade discovered that lithium was effective in the treatment of manodepressivity, lithium remains the gold standard in the treatement of bipolar disorder. For most patients lithium becomes a chronic, usually lifelong treatment. Despite a large number of studies and case descriptions confirming Garfinkel's initial findings that lithium can cause hypercalcaemia (abnormally high levels of calcium) and hyperparathyroidism (abnormally high activity in the parathyroid glands, shortened to HPT), the relationship still appears controversial. Lithium is believed to affect the calcium-sensing receptor (CSR) that is found in almost all the body's different tissues, but to a large extent in the parathyroid glands. It is still unknown if lithium initially demasks, i.e. reveals an already pathological parathyroid gland or causes pathological changes in the parathyroid gland, either as general hyperplasia (tissue enlargement) or as adenoma (benign tumour with glandular tissue as origin). The parathyroid gland isolates parathormone (PTH), one of two major hormones that takes care of calcium levels in the body. The calcium ion is of great importance for a wide range of physiological processes, not least within the nervous system, thus explaining why its concentration in serum is very carefully controlled. The other important calcium regulator is vitamin D. Its main task is to increase the absorption of calcium via dietary intake.
Hyperparathyroidism is a common disorder where a lot of research has been devoted to mapping the pathology of the disease and evaluating treatment options. The disease is estimated to have an incidence of 1 ‰ in I-countries, more common in postmenopausal women with a prevalence of 2-3%. Surgery remains as the recommended first-hand treatment where at least 98% of patients with HPT normalize their calcium balance after surgery and the majority remain cured. The operation can often be done relatively quickly with unilateral exploration and several clinics in the country intend to do utilise day surgery. Present understanding of hyperparathyroidism associated with concomitant lithium therapy (Lithium-associated hyperparathyroidism, LHPT) is inadequate. Bipolar disorder is estimated to occur in 1-2% of the population and recently it has been shown that LHPT occurs in 18% of lithium treated patients. Today more than 15,000 Swedes are treated with lithium. We still do not know what effects LHPT has on the patient's symptomatology, nor whether LHPT should be treated conservatively or with surgery. Approximately 300 surgical cases of LHPT have been reported in literature, with significant variations in results and pathological findings. The clearest study suggests that conventional surgery has poor long-term results with a high-frequency of persistent and recurrent hypercalcaemia (10). A large number of questions still need to be answered. Our primary purpose is to chart the physical and mental symptomatology in patients with LHPT, and evaluate whether or not a surgical treatment affects these symptoms in a positive way.

Projektspecifik information

Ämnesord

checked Endokrinologi och diabetes
checked Kirurgi
checked Psykiatri


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Studietyp

Prövning av behandling

Randomiserad studie

Ja

Diagnoskod för huvuddiagnos

E20-E35 Sjukdomar i andra endokrina körtlar

Multicenterstudie

Ja

Etikprövningsmyndighetens diarienummer

2014/435

Biobanksavtal

454

Inklusionsstatus

 Planerat antalAntal tillfrågadeScreen-failureAntal randominserade
n=3248 16

Vetenskaplig sammanfattning

The current study is, as far as we know, the first prospective randomised surgical study to evaluate the benefits of parathyroidectomy in lithium-treated patients with suspected LHPT. The study is ongoing, both in terms of evaluation and recruitment, so all results are highly preliminary. That said, a few points of interest seem to be emerging.

The biochemical characterisation of LHPT tends to display normal to moderately elevated calcium and often with a disproportionately elevated PTH, normal or increased S-PO 4 and Mg, normal or low (or indeed, very low) urinary calcium excretion rates . This latter characteristic may explain the absence of nephrolithiasis in LHPT patients . In addition, biochemical fluctuations do occur which, in turn, may confuse or impede the diagnosis or adequate management of the patient. This profile is in clear contrast to the fairly constant and, sometimes, continual progression of hypercalcaemia in patients with pHPT.

More radical surgery has been attributed with the increased possibility of cure, in terms of normocalcaemia, and was the motivating factor in aiming to do BNE with subtotal or total parathyroidectomy with autotransplantation. This approach is controversial, but since lithium-treatment is mostly life-long and LHPT is predominantly a MGD, there is a compelling need for this surgical strategy to be properly evaluated . In practice, more radical surgery is not always possible. One of the two patients in Group 1 (surgery) at latest follow-up could be classed as being normocalcaemic but also hyperparathyroid, with normal 25-OH-D status. An optimal first operation is, of course, paramount. Pre-operative Sestamibi scanning was, thus far, not shown to give instrumental guidance and one can question the benefit of routine imaging in this patient group if the surgical strategy is to be BNE. On the other hand, Carchman et al. did report better results with preoperative imaging.

Eleven (85%) of extirpated glands revealed the histopathological diagnosis hyperplasia. This confirms a series of antecedent studies characterising LHPT as MGD where the primary diagnosis is hyperplasia, most likely due to lithium’s universal effects . In this regard, it is somewhat bewildering why not all patients develop hypercalcaemia, some indeed remain euparathyroid throughout the entire treatment period with lithium. It must, therefore, be remembered that the patient may develop "true" pHPT, with the more prevalent histopathological diagnosis adenoma and fewer biochemical fluctuations, as in the other patient in Grp 1 at 12 months follow-up . This, of course, is my speculation.

Hypercalcaemia and HPT in lithium-treated patients is commonly detected as a result of screening and seldom due to control and management of symptoms. There is often significant doctor’s delay due to the indeterminate nature of symptoms and the interconnectivity with the individual patient’s affective disorder . Symptoms concerning tiredness and muscle fatigue frequently scored higher points in the symptom scale questionnaire in this study. Tentative indications are given at follow-up that the operated patients in this study may in general be feeling better, also shown in studies of seemingly asymptomatic pHPT patients , but these may also be transient effects of extra monitoring . It will be of great value and interest to evaluate well-being both at the end of the study period but also, for example, in five years’ time.

Involverade parter

Arbetsplats

Added workplaces

Regioner - Region Örebro Län - Hälso- och sjukvård - Område medicin och rehabilitering - Geriatriska kliniken workplace verified by Region Örebro län on 2018-06-14
Regioner - Region Jönköpings län - Specialiserad vård - Länssjukhuset Ryhov
Kirurgiska och psykiatriska klinikerna

Projektägare är huvudprövare eller ansvarig forskare

checked Ja


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Medarbetare i projektet

Mats B. Humble
Utredningssekreterare, Institutionen för neurovetenskap, Hälsovetenskaper, Område psykiatri, Universitetssjukvårdens forskningscentrum

Supervisor

Göran Wallin
Verksamhetschef, Naturvetenskap och Teknik, Kirurgiska kliniken
Johannes Järhult
professor, Kirurgiska kliniken, Länssjukhuset Ryhov

Slutrapport

Publikationer


Litiumassocierad hyperparatyreoidism: randomiserad studie för utvärdering av paratyreoidektomi hos litiumbehandlade patienter., from FoU Region Örebro län
http://www.researchweb.org/is/en/fourol/project/181871