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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0311
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 7 2722-2728
Copyright © 2008 by The Endocrine Society

High Risk of Hypopituitarism in Patients Who Recovered from Hemorrhagic Fever with Renal Syndrome

Marko Stojanovic, Sandra Pekic, Goran Cvijovic, Dragana Miljic, Mirjana Doknic, Marina Nikolic-Djurovic, Dragan Micic, Rajko Hrvacevic, Vidosava Nesic and Vera Popovic

Neuroendocrine Unit (M.S., S.P., G.C., D.Mil., M.D., M.N.-D., D.Mic., V.P.), Institute of Endocrinology, Diabetes and Diseases of Metabolism, University Clinical Center, Department of Nephrology (R.H.), Military Medical Academy, and Institute of Nephrology (V.N.), University Clinical Center, 11000 Belgrade, Serbia

Address all correspondence and requests for reprints to: Professor Vera Popovic, M.D., Ph.D., F.R.C.P., Neuroendocrine Unit, Institute of Endocrinology, University Clinical Center, Dr Subotica 13, 11000 Belgrade, Serbia. E-mail: popver{at}eunet.yu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Hemorrhagic fever with renal syndrome (HFRS) caused by hantaviruses, is a severe systemic infection, with acute shock, vascular leakage, hypotension, and acute renal failure. Pituitary ischemia/infarction and necrosis are known causes of hypopituitarism, often remaining unrecognized due to subtle clinical manifestations. Cases of hypopituitarism after HFRS were previously only sporadically reported.

Objective: The aim of this study was to determine, for the first time, the prevalence of hypopituitarism among HFRS survivors.

Subjects and Methods: In 60 adults (aged 35.8±1.3 yr) who recovered from HFRS 3.7 ± 0.5 yr ago (median 2 yr), assessment of serum T4, free T4, TSH, IGF-I, prolactin, cortisol, and testosterone (in males) was followed by insulin tolerance test and/or GHRH+GH-releasing peptide-6 stimulation tests.

Results: Severe GH deficiency was confirmed in eight of 60 patients (13.3%): in five with multiple pituitary hormone deficiencies (MPHDs) and isolated in three. Thyroid axis deficiency was confirmed in five of 60 patients (8.3%), all with MPHD. Hypothalamus-pituitary-adrenal axis deficiency was observed in six of 60 (10.0%); in five with MPHD and isolated in one. Gonadal axis deficiency was confirmed in seven of 56 male subjects (12.5%): five with MPHD and isolated in two. Overall six patients (10.0%) had a single pituitary deficit (three GH, two gonadal, and one adrenal), and five (8.3%) had MPHD. The prevalence of patients having any endocrine deficiency was 18% (11 of 60).

Conclusion: A high prevalence of hypopituitarism after recovery from HFRS is identified, with magnetic resonance imaging revealing atrophic pituitary and empty sella. Awareness is raised to neuroendocrine consequences of HFRS because unrecognized hypopituitarism significantly affects the physical and psychological well-being.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Hemorrhagic fever with renal syndrome is an acute infection caused by hantaviruses (HNTVs), RNA viruses of the family Bunyaviridae (1, 2). Hemorrhagic fever with renal syndrome found global attention during the Korean War in the 1950s when more than 3000 U.S. soldiers were severely affected with the mortality rate of 7% (1, 2). The HNTV serotypes Hantaan, Dobrava-Belgrade, Seoul, and Puumala cause hemorrhagic fever with renal syndrome, prevalent in Asia (Korea) and Europe (Finland and the Balkans), whereas in the Americas, related HNTVs cause hantavirus pulmonary syndrome, a different disease with partly overlapping clinical syndromes (3). Hemorrhagic fever with renal syndrome infection occurs via aerosolized excretions of virus-hosting rodents. Soldiers and field workers bear the occupational risk of infection, whereas refugees and aid workers share a high risk during military conflicts. During the Second World War, a large epidemic with 10,000 cases occurred in German troops in Finland (4), and reports of hemorrhagic fever with renal syndrome hazard for active military personnel continue to the present day (5). Hemorrhagic fever with renal syndrome is endemic in the Balkans (mainly Dobrava/Belgrade and Puumala serotypes). The first case of hemorrhagic fever with renal syndrome in former Yugoslavia was reported in 1952. Because the first identified epidemic of 1961 many outbreaks have been recorded (6, 7, 8). A nationwide epidemic of hemorrhagic fever with renal syndrome occurred in 1989 with 226 cases and mortality rate of 6.6% (9). The last hemorrhagic fever with renal syndrome outbreak in Serbia was recorded in 2006. Concerning the region of the Balkans, many reports focus on the military population as a group at highest risk (10, 11, 12, 13, 14).

The clinical course of hemorrhagic fever with renal syndrome is characterized by fever, circulatory collapse with hypotension, hemorrhages, and renal failure (2). The disease progresses through five phases: febrile, hypotensive, oliguric, diuretic, and convalescent. Most patients recover completely and complications are rare. Dobrava virus infections usually cause more severe symptoms with slower recovery. Reports on mortality in hemorrhagic fever with renal syndrome vary up to 15% (2). Immunopathogenic mechanisms are thought to be behind hemorrhagic fever with renal syndrome. A hallmark of hemorrhagic fever with renal syndrome is a capillary leak syndrome, causing edema and hemorrhage, suggesting that vascular endothelium is the prime target of virus infection. HNTVs may infect endothelial cells and monocyte/macrophages by cellular surface receptor (β3-integrin) involved in cell-to-cell adhesion, platelet aggregation, and maintenance of vascular barrier function (15, 16). Autopsy findings revealed no obvious damage in endothelial cells, suggesting that the capillary leakage is more likely caused by host immune responses via cytokine release (including TNF-{alpha}, IL-2, and interferon-{gamma}) rather than by endothelial cell lysis (17). A linkage between disease severity and major histocompatibility complex haplotype was also observed, with HLA-B8-DR3 haplotype being associated with more severe outcomes and HLA-b27 with milder forms of the disease (17).

Pituitary insufficiency associated with hemorrhagic fever with renal syndrome was reported sporadically with mechanisms remaining unclear (18, 19, 20, 21, 22, 23, 24). In most cases multiple pituitary hormone deficiency (MPHD) was reported, but a case with isolated hypogonadism was also described (25). Autopsy reports (regarding fatalities of the acute phase of hemorrhagic fever with renal syndrome) suggest slightly enlarged pituitary with signs of hemorrhage and necrosis and granulocyte infiltration of surrounding dura (26, 27). Direct viral invasion was confirmed in pituitary in both endocrine and endothelial cells (27). The analysis of 88 lethal outcomes of hemorrhagic fever with renal syndrome showed the occurrence of pituitary hemorrhage and necrotic foci in 75.5% of cases (28). Sporadic reports of computerized tomography (CT) and magnetic resonance imaging (MRI) in hemorrhagic fever with renal syndrome survivors developing hypopituitarism revealed pituitary atrophy and secondary empty sella (18, 21, 24). All of this suggests that patients with hemorrhagic fever with renal syndrome may suffer pituitary hemorrhage and subsequent necrosis with permanent pituitary failure. The aim of this study was to determine the prevalence of hypopituitarism in patients who recovered from hemorrhagic fever with renal syndrome.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Subjects were retrospectively recruited among patients previously treated for acute renal failure caused by hemorrhagic fever with renal syndrome at one of nephrology departments or infectious diseases departments of three medical centers in Belgrade (University Clinical Center, Military Medical Academy, KBC Zvezdara), three in central Serbia (Clinical Center Kragujevac, Medical Center Cacak, Medical Center Kraljevo), one in western Serbia (Medical Center Loznica), and one in southern Serbia (Clinical Center Nis). The inclusion criteria were serological confirmation of hemorrhagic fever with renal syndrome infection (indirect immunofluorescent assay, Torlak Institute, Belgrade) and a period of at least 6 months since full recovery from the acute hemorrhagic fever with renal syndrome infection. Eligible patients were approached without preselection and expressed their voluntary consent to participation. The study was approved by the Ethics Committee of University Clinical Center.

Studies

Subjects were assessed by physical examination, routine biochemical profile. and 24-h urine analysis to confirm full recovery from the acute phase of hemorrhagic fever with renal syndrome. Menstrual history was taken in all female subjects. The pituitary function was tested by basal hormonal profile at 0800 h after overnight fasting [T4, TSH, cortisol, FSH, LH, testosterone in males, and prolactin (PRL)] in all patients, with IGF-I in 54 patients. In patients with low-normal T4 levels, free T4 (FT4) levels were measured. Anterior pituitary reserve was tested with insulin tolerance test (ITT) in 54 patients, measuring GH, PRL, and cortisol at 0, 30, 60, 90, and 120 min after a bolus of 0.15 IU/kg of Actrapid-Insulin iv in six patients with contraindications for ITT (history of seizures or coronary heart disease), a stimulatory test with GHRH (Geref; Serono, Madrid, 1 µg/kg iv) plus GH-releasing peptide-6 (GHRP-6; Clinalfa, Laufelingen, Switzerland, 1 µg/kg iv) was performed, measuring GH at 0, 15, 30, 45, and 60 min. Three patients with isolated GH deficiency (GHD) were tested with both ITT and GHRH+GHRP-6 to confirm severe GHD. Four of patients with MPHD were evaluated by MRI of the hypothalamo-pituitary region, and one was evaluated by CT scan, being unable to undergo MRI (due to presence of a metallic foreign body).

Assays

All samples were stored at –80 C until analyzed. GH was measured by RIA (CIS BioInternational, Gif-sur-Yvette, France). IGF-I was measured by enzyme-labeled chemiluminescent immunometric assay (Immulite 2000; Siemens, Camberley, UK). The age-related normal reference ranges are: 116–358 ng/ml (20–25 yr), 117–329 ng/ml (26–30 yr), 115–307 ng/ml (31–35 yr), 109–284 ng/ml (36–40 yr), 101–267 ng/ml (41–45 yr), 94–252 ng/ml (46–50 yr), 87–238 ng/ml (51–55 yr), 81–225 ng/ml (56–60 yr), 75–212 ng/ml (61–65 yr), 69–200 ng/ml (66–70 yr). T4 (reference range 55–155 nmol/liter) was measured by RIA (INEP, Zemun, Serbia). FT4 (reference range 12–22 pmol/liter) was measured by immunoassay (Elecsys 1010/2010; Roche Diagnostics, Indianapolis, IN). TSH (reference range 0.17–4.05 mIU/liter) was measured by immunoradiometric assay (INEP). Cortisol (morning reference range 131–642 nmol/liter) was measured by RIA (CIS BioInternational). PRL (reference ranges: men, 90–37 0mIU/liter; premenopausal women, 130–700 mIU/liter) was measured by RIA (CIS BioInternational). FSH and LH (reference ranges for men: 1–9 and 1–5 mIU/ml, respectively; for premenopausal women in follicular phase of menstrual cycle: 3–8 and 1–7 mIU/ml, respectively) were measured by RIA (CIS BioInternational). Testosterone (male reference range 8.2–34.6 nmol/liter) was measured by RIA (CIS BioInternational).

Data analysis

The standard reference ranges were used to discriminate abnormal from normal results for: T4, FT4, TSH, cortisol, FSH, LH, testosterone (in males), and PRL. Age- and gender-specific normal ranges were used for interpreting IGF-I levels. Peak cortisol during ITT above 500 nmol/liter and/or an increase from baseline of 170 nmol/liter or more was interpreted as normal hypothalamus-pituitary-adrenal (HPA) axis response. A peak GH response of less than 3 µg/liter during ITT or less than 10 µg/liter during GHRH+GHRP-6 test was interpreted as severe GHD (29, 30). Stimulated PRL level was analyzed during the ITT.

Statistical analysis

Hormone concentrations are presented and analyzed as absolute values, as gh, cortisol and prolactin peaks during ITT, and as gh peak after ghrh+ghrp-6 (the maximum value of hormone measured after stimulus). All results are expressed as means±SE. The integrated areas of secretion [area under the curve (AUC)] were calculated using the trapezoidal method. Statistical analysis was performed using parametric t test and nonparametric Mann-Whitney U test. Correlation between various parameters in patients was analyzed using Spearman‘s rho correlation coefficient. SPSS software (SPSS for Windows, release 12.0) was employed for the analyses. P values of less than 0.05 were regarded as indicating statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Study population

Of the 60 patients tested, 56 (93.3%) were male and four (6.7%) were female (a distribution typical for hemorrhagic fever with renal syndrome epidemiology). The mean age at the time of the study was 35.8 ± 1.3 yr (median 33.5 yr; range 20–69 yr). The mean body mass index was 25.8 ± 0.4 kg/m2 (range, 17.7–33.1 kg/m2). Time from hemorrhagic fever with renal syndrome to study was 3.7 ± 0.5 yr (median 2 yr; range 6 months to 17 yr); the age of the patients at the time of acute hemorrhagic fever with renal syndrome infection was 32.1 ± 1.2 yr (range 17–58 yr). The acute hemorrhagic fever with renal syndrome infection, according to maximal values of serum creatinine (Cr) was: mild (Cr < 200 µmol/liter) in eight patients (13.3%), moderate (Cr of 200–900 µmol/liter) in 25 patients (41.7%), and severe (Cr > 900 µmol/liter) in 19 (31.7%) (without available data for Cr levels in eight patients). Dialysis was necessary in the acute hemorrhagic fever with renal syndrome in 35 patients (58.3%) (hemodialysis in 31; peritoneal dialysis in four), whereas 25 patients (41.7%) did not require dialysis. In five cases the acute hemorrhagic fever with renal syndrome was complicated by bacterial sepsis. None of the patients suffered diabetes insipidus during the acute phase of hemorrhagic fever with renal syndrome. All patients fully recovered from the acute phase of the hemorrhagic fever with renal syndrome and normalized renal functions. At the time of evaluation, three patients were on statins, two patients received antihypertensives (angiotensin-converting enzyme inhibitors), and three patients received both statins and antihypertensives (angiotensin-converting enzyme inhibitors or Ca antagonists).

Somatotropic axis

Of the 53 patients who underwent ITT, severe GHD was found in four. Of the six patients who underwent GHRH+GHRP-6 test, three were with severe GHD. One patient was diagnosed as severe GHD without provocative testing in the context of MPHD and low IGF-I (31). Overall, severe GHD was confirmed in eight (13.3%) patients. Isolated severe GHD was found in three of eight patients, whereas the other five had MPHD. Patients with isolated GHD were tested with both tests to confirm severe GHD, and all also had low IGF-I levels.

Comparison of GHD patients with non-GHD patients (i.e. GH sufficient) is presented in Table 1Go. Peak GH response to the ITT correlated significantly with the occurrence of sepsis in the acute hemorrhagic fever with renal syndrome (r = 0.444; P = 0.009), severity of renal insufficiency (according to the necessity for the dialysis; r = 0.324; P = 0.019), and minimal platelet count in the acute hemorrhagic fever with renal syndrome (r = 0.617, P = 0.001). GHD was more frequent when the acute hemorrhagic fever with renal syndrome was complicated by sepsis, those necessitating dialyses, and those with lower platelet count during the acute hemorrhagic fever with renal syndrome. IGF-I levels correlated significantly with the occurrence of sepsis in the acute hemorrhagic fever with renal syndrome (r = 0.354; P = 0.011).


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  		TABLE 1. Comparison of severely GHD and GH-sufficient (GHS) patients recovered from hemorrhagic fever with renal syndrome (HFRS)

 
Thyroid axis

T4 and TSH levels were both below normal in five of 60 patients (8.3%), all with MPHD. In three patients with low-normal T4, FT4 levels were normal. T4 levels in all hemorrhagic fever with renal syndrome patients were significantly lower in GHD, compared with non-GHD, patients (Table 1Go). T4 levels correlated significantly with the occurrence of hemorrhage (r = 0.286; P = 0.031) and sepsis (r = 0.317; P = 0.015) in the acute hemorrhagic fever with renal syndrome.

Adrenal axis

HPA axis deficiency was observed in six of 60 patients (10.0%). Basal cortisol levels were below normal in five of 60 patients (8.3%), with low peak cortisol levels during ITT, all with MPHD. Additionally, one patient had low-normal morning cortisol level (230 nmol/liter), with inadequate response to ITT (<500 nmol/liter) and was diagnosed as isolated HPA axis deficiency. Baseline cortisol levels, peak cortisol level during ITT, and integrated cortisol secretion during ITT [area under the curve (AUC)] were significantly lower in GHD, compared with non-GHD, patients (Table 1Go).

Gonadal and lactotropic axes

Testosterone level was below normal in seven (12.5%) of 56 male subjects. Of these, five had MPHD and two had isolated gonadal axis deficiency. Testosterone levels were significantly lower in GHD, compared with non-GHD patients (Table 1Go). Testosterone levels correlated significantly with the minimal platelet count during the acute hemorrhagic fever with renal syndrome (r = 0.292; P = 0.04).

All four female patients had regular menstrual cycles.

Of five patients with MPHD, baseline PRL level was low in four, whereas in one, PRL levels were low normal and did not change during ITT. Peak PRL level during ITT and integrated PRL secretion during ITT (AUC) were significantly lower in GHD, compared with non-GHD patients (Table 1Go). None of the patients in this study had elevated basal PRL levels.

Combined abnormalities

Overall, 49 patients (81.7%) had no endocrine abnormalities, six patients (10.0%) had a single pituitary deficit (three GH, two gonadal, and one adrenal), and five (8.3%) had MPHD (Figs. 1Go and 2Go). No subjects were treated with DDAVP or exhibited symptomatic polyuria. The prevalence of patients having any endocrine deficiency among this group of hemorrhagic fever with renal syndrome survivors was 18.3% (11 of 60).


Figure 1
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  		FIG. 1. Percentage of normal pituitary function, loss of one axis, and loss of multiple pituitary axes in patients recovered from hemorrhagic fever with renal syndrome.

 

Figure 2
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  		FIG. 2. Distribution of pituitary hormone deficiencies in patients recovered from hemorrhagic fever with renal syndrome.

 
The degree of endocrine deficiency correlated significantly with the occurrence of sepsis in the acute hemorrhagic fever with renal syndrome (r = 0.293; P = 0.026), severity of renal insufficiency (according to the necessity for the dialysis; r = 0.324; P = 0.012), and minimal platelet count during the acute hemorrhagic fever with renal syndrome (r = 0.359; P = 0.008). Hypopituitarism was more frequent in those with hemorrhagic fever with renal syndrome complicated by sepsis, those necessitating dialyses, and those with lower platelet count in the acute hemorrhagic fever with renal syndrome. Comparison of relevant clinical and laboratory findings from the acute hemorrhagic fever with renal syndrome in patients with single or multiple pituitary hormone deficiency vs. those with no abnormalities is presented in Table 2Go.


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  		TABLE 2. Relevant clinical and laboratory findings from the acute hemorrhagic fever with renal syndrome in patients with single or multiple pituitary hormone deficiency vs. those with normal anterior pituitary function

 
Neuroimaging of the hypothalamo-pituitary region

Four of five patients with MPHD were further evaluated by MRI of the hypothalamo-pituitary region, revealing empty sella with pituitary atrophy (Fig. 3Go, A and B). In the fifth MPHD patient, CT revealed no pituitary abnormalities.


Figure 3
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  		FIG. 3. A and B, Sagittal and coronal section on magnetic resonance scan showing an empty sella and atrophic pituitary gland in a patient with MPHD after hemorrhagic fever with renal syndrome [Reproduced with permission from Pekic S, Cvijovic G, Stojanovic M, Kendereski A, Micic D, Popovic V: Endocrine 26:79–82, 2005 (24 )].

 
Clinical history of five patients with MPHD

The first of the MPHD patients, a male, evaluated 1.5 yr after hemorrhagic fever with renal syndrome, reported weakness, apathy, cold intolerance, loss of appetite, hypotension, loss of libido, and decrease in facial, axillary, and pubic hair, all dating back to after recovery from acute hemorrhagic fever with renal syndrome. He was treated for resistant hyperlipidemia, which developed 1 yr after hemorrhagic fever with renal syndrome. On physical examination, he presented with dry skin, hypotension, bradycardia, loss of facial, pubic, and axillary hair, and reduced testicular volume. The second patient, a male, evaluated 2 yr after hemorrhagic fever with renal syndrome exhibited hyperlipidemia resistant to treatment and on physical examination presented with bradycardia and reduced testicular volume. The third patient, male, evaluated 2 yr after hemorrhagic fever with renal syndrome, reported severe loss of libido and impotence after acute hemorrhagic fever with renal syndrome, reduction in facial, pubic and axillary hair, dry skin, and cold intolerance. On physical examination, he presented with dry skin, hypotension, bradycardia, loss of facial, pubic, and axillary hair, and reduced testicular volume. The fourth patient, a male, evaluated 11 yr after hemorrhagic fever with renal syndrome, reported loss of appetite, weakness, apathy, loss of libido, and decrease in facial, axillary, and pubic hair, dating back to after recovery from acute hemorrhagic fever with renal syndrome and progressing since that time. On physical examination, he presented with pale, dry skin, hypotension, loss of facial, pubic, and axillary hair. The fifth patient, a male, evaluated 6 months after acute hemorrhagic fever with renal syndrome exhibited hyperlipidemia and weakness. On physical examination, he was without significant findings other than hypotension and bradycardia.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is, to the best of our knowledge, the first report of a rather high prevalence of hypopituitarism in patients recovered from hemorrhagic fever with renal syndrome, a disease endemic in the Balkans with a substantial annual incidence.

Hypopituitarism can remain undetected due to nonspecific symptoms and signs (tiredness, cold intolerance, weakness, hypotension, decreased muscular strength, loss of libido, loss of pubic and axillary hair, pallor, bradycardia, apathy, and mental and cognitive disturbances), and it is sometimes revealed only after targeted hormonal investigation (32).

The GH-IGF-I axis is the first and most often impaired in a pituitary failure. In this study severe GHD was confirmed in eight patients (13.3%) by either ITT or GHRH+GHRP-6. Five GHD subjects had MPHD, and GH stimulation test may have been unnecessary (30). Isolated GHD was diagnosed in another three subjects (5.0%). In real life there is a spectrum from normal through partial to severe GHD, but GH therapy in adults is currently offered only for severe GHD (29).

Gonadotropin secretion is typically the second most vulnerable, and in this study it was confirmed in seven subjects (11.7%, all male) evaluated at an average of 2 yr after hemorrhagic fever with renal syndrome. Five of these had MPHD and two had isolated gonadal axis deficiency.

Thyroid axis assessment has revealed insufficiency in five of 60 subjects (8.3%), all with MPHD.

HPA axis assessment revealed the prevalence of adrenal insufficiency in six of 60 (10.0%). Basal cortisol levels were below normal with inadequate increase during ITT in five patients with MPHD (8.3%). In one patient (1.7%), isolated HPA axis deficiency was diagnosed with a low peak cortisol response to ITT.

All patients with hypopituitarism have fully recovered renal function after severe acute hemorrhagic fever with renal syndrome. Time since the acute hemorrhagic fever with renal syndrome in hypopituitaric patients ranged from 6 months to 11 yr (average of 2 yr), indicating that most patients were diagnosed late, long after hemorrhagic fever with renal syndrome. Common for all patients were nonspecific signs and symptoms, hallmarked in most of them by resistant hyperlipidemia, which were not recognized as hypopituitarism. This delay in diagnosis had important implications for patients’ health and sense of well-being. MRI of the sellar region in our patients revealed pituitary atrophy with an empty sella. The presence of an idiopathic empty sella cannot be excluded, whereas anamnestic, clinical, laboratory, and neuroimaging data make other causes of hypopituitarism, independently of hemorrhagic fever with renal syndrome, unlikely.

Today the most common cause of hypopituitarism are tumors, damaging the hormone-producing pituitary cells or interfering with their hypothalamic control; other causes such as autoimmune inflammation of the pituitary, infection, trauma (33), and granuloma are much rarer. In 1914 Simmonds (34) described an autopsy finding in a 46-yr-old woman who died from chronic hypopituitarism 11 yr after severe puerperal sepsis, revealing severe pituitary atrophy that was then attributed to bacterial embolization. In 1937 Sheehan (35) postulated that pituitary necrosis was an infarction caused by ischemia, rather than puerperal sepsis or mycotic/bacterial emboli. Pituitary necrosis unrelated to postpartum ischemic infarction can occur in cases of raised intracranial pressure, pituitary stalk damage, acute pituitary apoplexy, traumatic brain injury, massive stroke, and subarachnoid hemorrhage. Increased incidence of pituitary necrosis has also been reported in patients with diabetes mellitus, after cardiac surgery, patients on assisted ventilation, and patients after acute hemorrhagic fever, as was the case in our patients. Pituitary cannot regenerate and necrotic cells are replaced by scar tissue. Normal pituitary function can be supported until about 50% of the gland remains intact, whereas partial and complete hypopituitarism follow the loss of 75 and 90% (respectively) of the gland (36).

The anterior pituitary is among the most common sites of hemorrhage in hemorrhagic fever with renal syndrome possibly because of its anatomical localization and vascularization (37, 38). The anterior pituitary lobe receives only 10–20% of its blood supply from superior and inferior hypophyseal arteries, whereas the remaining 80–90% is provided by hypophyseal venous portal circulation. Postmortem analysis after hemorrhagic fever with renal syndrome revealed hemorrhage and necrosis in the anterior pituitary in 50–100% of cases (37, 38). These data concur with the first report of necrosis and hemorrhage in pituitary in 60% of fatalities in the hypotensive phase of hemorrhagic fever with renal syndrome and in almost all who died in the oliguric phase (39). The atrophic changes in pituitary with consecutive hypopituitarism in our patients are similar to those previously sporadically described (21). It is possible that hypopituitarism is more common than is recognized and that it should be considered in all patients who recovered from severe hemorrhagic fever with renal syndrome. The mechanisms of pituitary hemorrhage and necrosis are still unclear, but in the absence of evidence of vascular occlusion, vasospasm after shock is blamed. Hypopituitarism may be caused by hemorrhage (due to low platelet count and/or increased microvascular permeability), ischemia (during hypovolemic shock and oliguric phase of hemorrhagic fever with renal syndrome), and necrosis due to direct cytopathic viral effect and bacterial embolization (in patients with sepsis). Finally fibrosis and pituitary atrophy develop resulting in hypopituitarism.

In conclusion, a high prevalence of hypopituitarism (18.3%) is found in this study in patients who recovered from hemorrhagic fever with renal syndrome many years ago. Hypopituitarism is often undetected or diagnosed late, and this has severe implications on patients’ health and sense of well-being. These findings strongly suggest that patients who have recovered from hemorrhagic fever with renal syndrome are at risk for developing pituitary failure as a late sequela and should be systematically investigated and treated if necessary. Particular awareness should be raised concerning endemic regions such as the Balkans.


   Acknowledgments
 
The authors thank Professor N. Dimkovic, M.D., Ph.D. (Nephrology Department, KBC Zvezdara, Belgrade); Professor V. Lezajic, M.D., Ph.D. (Institute of Nephrology, University Clinical Center, Belgrade); Professor S. Nikolic, M.D., Ph.D., Professor B. Brmbolic, M.D., Ph.D., and Professor M. Pelemis, M.D., Ph.D. (Institute for Infectious Diseases, University Clinical Center, Belgrade); and M. Lazarevic, M.D., Ph.D. (Nephrology Department, Clinical Center Kragujevac) for their help in recruitment of the patients included in this study, and B. Bozovic, M.D., Ph.D. (Torlak Institute, Belgrade) for providing the serological data for the study patients.


   Footnotes
 
This work was supported by a grant from the Ministry of Science of the Republic of Serbia (Project 145019).

Disclosure Statement: M.S., S.P., G.C., D.Mil., M.D., M.N.-D., D.Mic., R.H., and V.N. have nothing to declare. V.P. received lecture fees from Pfizer.

First Published Online April 22, 2008

Abbreviations: AUC, Area under the curve; Cr, creatinine; CT, computerized tomography; FT4, free T4; GHD, GH deficiency; GHRP-6, GH-releasing peptide-6; HNTV, hantavirus; HPA, hypothalamus-pituitary-adrenal; ITT, insulin tolerance test; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging; PRL, prolactin.

Received February 8, 2008.

Accepted April 16, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Schmaljohn CS, Hasty SE, Dalrymple JM, Leduc, JW, Lee HW, von Bonsdorff CH, Brummer-Korvenkontio M, Vaheri A, Tsai TF, Regnery HL 1985 Antigenic and genetic properties of viruses linked to hemorrhagic fever with renal syndrome. Science 227:1041–1044[Abstract/Free Full Text]
  2. Muranyi W, Bahr U, Zeier M, van der Woude FJ 2005 Hantavirus infection. J Am Soc Nephrol 16:3669–3679[Free Full Text]
  3. Peters CJ, Simpson GL, Levy H 1999 Spectrum of hantavirus infection: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Annu Rev Med 50:531–545[CrossRef][Medline]
  4. Stuhlfauth, K 1943 Bericht uber ein neues schlammfieberahnliches krankenheitsbild bei deutschen truppen in Lappland. Dtsch Med Wochenschr 69:439–443
  5. Clement J, Underwood P, Ward D, Pilaski J, Leduc J 1996 Hantavirus outbreak during military manoeuvres in Germany. Lancet 347:336
  6. Zivaljevic V, Adanja B, Obradovic M, Lukac V 1995 Epidemiologic characteristics of hemorrhagic fever with renal syndrome in Serbia, 1979–1992. Vojnosanit Pregl 52:142–145[Medline]
  7. Jovanovic D, Skataric V, Kovacevic Z, Maric M, Gligic A, Romanovic R 1997 Acute renal failure in hemorrhagic fever with renal syndrome. Vojnosanit Pregl 54:453–458[Medline]
  8. Papa A, Bojovic B, Antoniadis A 2006 Hantaviruses in Serbia and Montenegro. Emerg Infect Dis 12:1015–1018[Medline]
  9. Gligic A, Stojanovic R, Obradovic M, Hlaca D, Dimkovic N, Diglisic G, Lukac V, Ler Z, Bogdanovic R, Antonijevic B 1992 Hemorrhagic fever with renal syndrome in Yugoslavia: epidemiologic and epizootiologic features of a nationwide outbreak in 1989. Eur J Epidemiol 8:816–825[CrossRef][Medline]
  10. Lukac V, Dokic M, Rakovic-Savcic L, Diglisic G, Gligic A, Drndarevic D, Obradovic M 1992 Epidemiologic characteristics of hemorrhagic fever with renal syndrome in a military population. Vojnosanit Pregl 49:201–205[Medline]
  11. Hukic M, Kurt A, Torstensson S, Lundkvist A, Wiger D, Niklasson B 1996 Haemorrhagic fever with renal syndrome in north-east Bosnia. Lancet 347:56–57[Medline]
  12. Markotic A, Leduc JW, Hlaca D, Rabatic S, Sarcevic A, Dasic G, Gagro A, Kuzman I, Barac V, Avsic-Zupanc T, Beus I, Dekaris D 1996 Hantaviruses are likely threat to NATO forces in Bosnia and Herzegovina and Croatia. Nat Med 2:269–270[CrossRef][Medline]
  13. Bugert JJ, Welzel TM, Zeier M, Darai G 1999 Hantavirus infection-haemorrhagic fever in the Balkans—potential nephrological hazards in the Kosovo War. Nephrol Dial Transplant 14:1843–1844[Free Full Text]
  14. Sanchez Jr JL, Craig SC, Kohlhase K, Polyak C, Ludwig SL, Rumm PD 2001 Health assessment of U.S. military personnel deployed to Bosnia-Herzegovina for operation joint endeavor. Mil Med 166:470–474[Medline]
  15. Gavrilovskaya IN, Brown EJ, Ginsberg MH, Mackow ER 1999 Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by β3 integrins. J Virol 73:3951–3959[Abstract/Free Full Text]
  16. Hayasaka D, Maeda K, Ennis FA, Terajima M 2007 Increased permeability of human endothelial cell line EA.hy926 induced by hantavirus-specific cytotoxic T lymphocytes. Virus Res 123:120–127[CrossRef][Medline]
  17. Terajima M, Hayasaka D, Maeda K, Ennis FA 2007 Immunopathogenesis of a hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome: do CD8+ t cells trigger capillary leakage in viral hemorrhagic fevers? Immunol Lett 113:117–120[CrossRef][Medline]
  18. Lim TH, Chang KH, Han MC, Chang YB, Lim SM, Yu YS, Chun YH, Lee JS 1986 Pituitary atrophy in Korean (epidemic) hemorrhagic fever: CT correlation with pituitary function and visual field. Am J Neuroradiol 7:633–637[Abstract]
  19. Settergren B, Boman J, Linderholm M, Wistrom J, Hagg E, Arvidsson PA 1992 A case of nephropathia epidemica associated with panhypopituitarism and nephrotic syndrome. Nephron 61:234–235[Medline]
  20. Forslund T, Saltevo J, Anttinen J, Auvinen S, Brummer-Korvenkontio M, Korhonen A, Poutiainen M 1992 Complications of nephropathia epidemica: three cases. J Intern Med 232:87–90[Medline]
  21. Suh DC, Park JS, Park SK, Lee HK, Chang KH 1995 Pituitary hemorrhage as a complication of hantaviral disease. Am J Neuroradiol 16:175–178[Abstract]
  22. Park JE, Pyo HJ 1996 Delayed onset of diuresis in a patient with acute renal failure due to hemorrhagic fever with renal syndrome who also developed anterior hypopituitarism. Clin Nephrol 6:141–145
  23. Kim NH, Cho JG, Ahn YK, Lee SU, Kim KH, Cho JH, Kim HG, Kim W, Jeong MH, Park JC, Kang JC 2001 A case of torsade de pointes associated with hypopituitarism due to hemorrhagic fever with renal syndrome. J Korean Med Sci 16:355–359[Medline]
  24. Pekic S, Cvijovic G, Stojanovic M, Kendereski A, Micic D, Popovic V 2005 Hypopituitarism as a late complication of hemorrhagic fever. Endocrine 26:79–82[CrossRef][Medline]
  25. Saltevo J, Forslund T 1992 Epidemic nephritis followed by hypogonadism. Duodecim 108:494–496[Medline]
  26. Valtonen M, Kauppila M, Kotilainen P, Lähdevirta J, Svartbäck CM, Kosunen O, Nurminen J, Sarkkinen H, Brummer-Korvenkontio M 1995 Four fatal cases of nephropathia epidemica. Scand J Infect Dis 237:515–517
  27. Hautala T, Sironen T, Vapalahti O, Paakko E, Sarkioja T, Salmela PI, Vaheri A, Plyusnin A, Kauma H 2002 Hypophyseal hemorrhage and panhypopituitarism during Puumala virus infection: magnetic resonance imaging and detection of viral antigen in the hypophysis. Clin Infect Dis 35:96–101[CrossRef][Medline]
  28. Klebanov IUA 1990 Analysis of fatal outcome in hemorrhagic fever with renal syndrome. Klin Med (Mosk) 68:64–67
  29. Ho KK; GH Deficiency Consensus Workshop Participants 2007 Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol 157:695–700[Abstract/Free Full Text]
  30. Popovic V, Leal A, Micic D, Koppeschaar HP, Torres E, Paramo C, Obradovic S, Dieguez C, Casanueva FF 2000 GH-releasing hormone and GH-releasing peptide-6 for diagnostic testing in GH-deficient adults. Lancet 356:1137–1142[CrossRef][Medline]
  31. Hartman ML, Crowe BJ, Biller BM, Ho KK, Clemmons DR, Chipman JJ, HyposCCS Advisory Board; U.S. HypoCCS Study Group 2002 Which patients do not require a GH stimulation test for the diagnosis of adult GH deficiency? J Clin Endocrinol Metab 87:477–485[Abstract/Free Full Text]
  32. Vance Ml 1994 Hypopituitarism. N Engl J Med 330:1651–1662[Free Full Text]
  33. Popovic V, Pekic S, Pavlovic D, Maric N, Jasovic-Gasic M, Djurovic B, Medic Stojanoska M, Zivkovic V, Stojanovic M, Doknic M, Milic N, Djurovic M, Dieguez C, Casanueva FF 2004 Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress. J Endocrinol Invest 27:1048–1054[Medline]
  34. Simmonds, M 1914 Uber hypophysisschwund mit todlichem ausgang. Dtch Med Wschr 40:322–323
  35. Sheehan HL 1937 Post-partum necrosis of the anterior pituitary. J Path Bact 45:189–214[CrossRef]
  36. Kovacs K 2003 Sheehan’s syndrome. Lancet 361:520–522[CrossRef][Medline]
  37. Lukes RJ 1952 Pathology of thirty-nine fatal cases of epidemic hemorrhagic fever. Am J Med 16:639–650
  38. Hullinghorst RL, Steer A 1953 Pathology of epidemic hemorrhagic fever. Ann Intern Med 38:77–101[Abstract/Free Full Text]
  39. Lee HW, van der Groen G 1989 Hemorrhagic fever with renal syndrome. Prog Med Virol 36:62–102[Medline]



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C. Jost, R. Krause, W. Graninger, and K. Weber
Transient hypopituitarism in a patient with nephropathia epidemica
BMJ Case Reports, June 21, 2009; 2009(jun21_1): bcr0220091538 - bcr0220091538.
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