Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency

Abstract

The prevalence of malignant hypertension has clearly fallen with the advent of anti-hypertensive medication but has remained stable over the past 30–40 years in spite of progress in diagnosis and management of hypertension. A diagnosis of malignant hypertension is usually based on the association of severely elevated blood pressure with a Keith and Wagener stage III or IV retinopathy. We believe that this definition can be reconsidered for several reasons. Although simple and pragmatic, this definition corresponds to a time when there were few techniques for assessment of hypertensive target organ involvement, and does not take into account involvement of kidney, brain and heart; whereas the overall prognosis largely depends on how much they are affected. On the contrary, the acute blood pressure level and especially diastolic should not be a hard diagnostic criterion as it does not itself constitute the prognosis of the condition. We propose to consider that malignant hypertension with retinopathy is only one of a number of possible presentation(s) of acute hypertension with multi organ damage (hypertension multi organ damage (MOD)) and that the recognition of these hypertensive emergencies, when retinopathy is lacking, be based on acute elevation of BP associated with impairment of at least three different target organs. The objective of a new and expanded definition is to facilitate recognition of these true emergencies. The condition is more common than usually perceived and would have a much worse prognosis than the usual forms of hypertension. Early recognition and management of hypertension-MOD are fundamental to any improvement in prognosis.

Introduction

Hypertension is a major risk factor for cardiovascular events. Over time, hypertension may be accompanied by impairment of various target organs, mainly the brain, heart and kidney. Lesions of these organs form the overall prognosis of hypertension. These processes are usually drawn out and depend on the blood pressure (BP) levels, its variability and the presence of other risk factors. There is, however, a particular form of hypertension characterized by the speed and the gravity of its impact. This form of hypertension, which may be of essential or secondary origin, may be the first sign or may be superimposed on an existing hypertension.1 This form of hypertension is referred to as ‘malignant or accelerated hypertension2’ and is characterized by multi organ involvement appearing over a short period of time, from a few weeks to a few months. Malignant hypertension (MH) has a very poor prognosis in the absence of treatment, and needs to be managed quickly by specialized care to limit its consequences. However, even with prompt treatment, the residual risk for end stage renal disease and cardiovascular complications remains high.3, 4, 5 Despite the urgent and serious character of MH, it remains little studied and as yet there are few recommendations from the hypertension societies. A systematic review from Pak et al.6 concluded as follow: ‘Despite numerous national and international guidelines for chronic hypertension, the common problem of acute hypertension is neglected in the literature. Results from the STAT registry and other studies demonstrate that acute severe hypertension in the hospital setting has high rates of mortality and morbidity, especially with new or worsening endorgan damage…’

So it is probably time to re-evaluate the scope of acute and malignant hypertension and try to improve its outcome.

Epidemiology and new definitions

MH has a low prevalence in the general population, with an annual incidence rate of around 5/100.000 in the Caucasian population and 10/100.000 in the African origin populations.7, 8 Its prevalence has clearly fallen with the advent of anti-hypertensive medication but has remained stable over the past 30–40 years in spite of progress in the overall management of hypertension.9, 10 Because the clinical symptoms of MH are non specific and many patients with very high BP values may not receive funduscopy, the prevalence of MH is probably higher.

Initially, MH had an extremely severe prognosis with an 80% mortality at 2 years.11 Earlier diagnosis and treatment, particularly with the development of new anti-hypertensive drugs improved this prognosis,10 but these patients still appear to have a greater risk of complications than those with the other forms of hypertension.5, 12 The major determining factor in the prognosis does not appear to be the level of BP itself, but rather, the severity of the renal impairment.13 The fact that the initial BP is not a key component in the final prognosis casts some doubt on the diagnostic criteria habitually employed to define MH.14

At present, a diagnosis of MH is based on the association of severely elevated BP (for example, diastolic BP>130 mm Hg) with severe hypertensive retinopathy. Although simple and pragmatic, this definition is old and corresponds to a time when there were few techniques for assessment of hypertensive target organ damage (TOD). This is particularly true for the heart, which in a context of MH often shows particular characteristics on detailed echocardiographic examination.15 Tomodensitometric scanning and MRI have also contributed to the evaluation of cerebral involvement. It is probably no longer advisable to wait until ocular fundus stage 3 or 4 in both eyes before instigating treatment and management in patients with hypertension and important TOD. The usual definition of MH also does not take into account other TOD, whereas the overall prognosis largely depends of its importance.

The 2013 ESH/ESC guidelines for the management of arterial hypertension16 are a perfect illustration of the small place left to MH in guidelines. MH is addressed in a short paragraph and defined as the presence of very high BP (no cutoff value) associated with ischaemic TOD (retina, kidney and heart or brain). This definition is certainly true but too imprecise to be really helpful. These guidelines also point out the still poor prognosis of MH and the fact that no good controlled study has been conducted. However, the low incidence of MH cannot be presented as the only reason, considering the imprecision of diagnostic criteria and the poor attention left to it.

Consequently, we feel that these real hypertensive emergencies need to be redefined and diagnosis criteria stated more precisely. The acute TOD preceding the historical form of MH should perhaps not be referred to as ‘malignant’ with its reference to cancer as it does not correspond to the current prognosis. The interest of redefining this clinical entity would be to accelerate the diagnosis and to improve therapeutic management to limit the impact on major organ health.

Making a diagnosis of hypertension with multi organ damage: hypertension-MOD

We propose to requalify these hypertensive emergencies (which include MH) as hypertension-MOD. For historical and practical reasons, the simple and pragmatic diagnosis of MH should remain based on high BP with severe retinopathy but MH should be considered as one of a number of possible presentations of hypertension-MOD.

The absence of fundus abnormalities does not rule out hypertension-MOD for several reasons. First, unilateral fundus lesions may have the same prognosis.17 This indicates that there are individual differences in the baro-resistance of eyes to high BP and that these differences may vary from eye to eye but also probably between subjects. Second, various lesions in the ocular fundus, that is, haemorrhages, exudates with or without papilloedema or isolated papilloedema17 have the same prognosis thereby lumping together malignant and accelerated hypertension in the same pathological entity. Third, hypertensive retinopathy may be lacking in a significant proportion of patients with severe hypertensive encephalopathy.18 Moreover, ocular fundus examinations are not always easily available as in some healthcare systems, they are only conducted by ophthalmologic specialists, which in turn lead to a delay in management.

We propose that the recognition of these hypertensive emergencies in hypertension-MOD, when retinopathy is lacking, be based on elevation of BP associated with impairment of at least three different organs, as summarized in Table 1 in an acute presentation. The clinical presentations will differ according to the organ, that is most impaired producing the symptoms enabling diagnosis.

Table 1 Main criteria for target organ involvement in hypertension-MOD

Elevation of BP

This may occur as an increase in BP in patients under anti-hypertensive treatment or in patients not recognized as being hypertensive. In the chronic hypertensive, withdrawal of the anti-hypertensive treatment and in particular blockers of the renin angiotensin system may underlie this onset. Unlike conventional chronic hypertension, it is often accompanied by clinical signs: tiredness, weight loss, headaches, ocular disorders, thirst, chest pains, nausea or vomiting and dyspnoea on exertion. However, these signs are non specific.

Multi organ damage

The objective of our modern definition is to enlarge the indication of a prompt strategy of BP control even when there is no severe hypertensive retinopathy. In our clinical practice, these severe forms of hypertension have a higher prevalence than classical MH.

Brain

A neurological deficit is a key factor in the detection of MH in a large proportion of cases (around 30%). However, the neurological impairment may be asymptomatic. Only systematic MRI can show extensive white matter lesions and microbleeds. These images are non specific but their presence in the context of high BP and other TOD is evocative, especially in patients under 60-years old. Posterior reversible encephalopathy syndrome is probably more specific but not often present. We certainly do not suggest that brain MRI should be systematically performed in front of all hypertensives emergencies but the association of several arguments pleading for hypertension-MOD should lead to consider the interest of performing this investigation, as sometimes the brain lesions are asymptomatic but may have an important prognostic value.19

Kidney

Renal abnormalities are common (60–70%)3 and include elevated serum creatinine and proteinuria, usually modest (about 1 g/24 h), but sometimes accompanied by microscopic haematuria. There is also reduced serum potassium stemming from stimulation of the renin-angiotensin-aldosterone system, which must appear very significant in the presence of renal failure. Nonetheless, the degree of renal impairment and persistence of proteinuria will largely condition the outcome of the patient,3, 4 prompting rapid control of BP to protect renal function.20 With prompt recognition and adequate BP control renal function may recover, even in patients who initially needed dialysis.21

Heart

Left ventricle (LV) involvement is frequent and often severe. It can be identified from specific electrocardiogram abnormalities: increase in the voltage of the QRS complexes, indicative of an increase in LV mass often associated with repolarization changes (strain pattern) indicative of ischaemia. Echocardiography usually shows an increase in LV mass,22 often marked. In our experience15 average left ventricular mass indexed for height2.7 was 78 g m−2.7 at acute phase when usual cutoff for left ventricular hypertrophy (LVH) is around 50 g m−2.7. Echocardiography can also evaluate systolic function, especially global longitudinal strain, often impaired at acute phase when LV ejection fraction is still normal.15 A modest but significant elevation in troponin, also indicative of myocardial ischaemia, is also frequent in the Bordeaux cohort but was not systematically investigated in other series. Nonetheless, some patients with MH may present with no LVH evident.

Thrombothic microangiopathy

Hypertensive damage of the vasculature may cause fibrinoid necrosis with thrombotic occlusions of arterioles. This may lead to consumption of platelets and fragmentation of erythrocytes, observed in 25% of patients with MH.21 Occlusion of arterioles in the kidney aggravates renal ischaemia and further activates the renin-angiotensin system, thereby sustaining BP elevation. Presence of haemolysis and low platelet count is an important predictor of renal failure and possible recovery.

Diagnostic difficulties

One of the diagnostic difficulties is the demonstration of an acute or subacute development of the lesions. Indeed, poorly controlled chronic hypertensive patients may develop LVH along with impaired renal function, which may obscure a diagnosis of hypertension-MOD.

Some elements should help make this distinction:

  1. a)

    Clinical presentation: conventional hypertension is largely asymptomatic. Marked hypertension combined with symptoms associated with bad tolerance (tiredness, thirst and headaches) should prompt a search for hypertension-MOD.

  2. b)

    Patient history: previous laboratory findings should be scrutinized along with electrocardiogram to identify recent deteriorations in favour of hypertension-MOD.

  3. c)

    TOD needs to be investigated: once the diagnosis is envisaged, it needs to be confirmed by complete work-up which will add further elements in favour of the diagnosis. An ocular fundus examination is necessary for a definitive diagnosis. Nevertheless, one should not wait for the ocular fundus findings before instigating treatment as a normal fundus does not rule out the diagnosis. After all, fundal changes may persist for weeks.

Another difficulty is to distinguish between acute nephrologic syndrome with secondary hypertension and hypertensive ‘malignant’ nephroangiosclerosis.

  1. a)

    Scleroderma renal crisis occurs in 5–20% of patients with diffuse cutaneous sclerodermia. Scleroderma renal crisis is very similar to hypertension-MOD and treated the same way with angiotensin-converting-enzyme inhibitors. About 25–50% of these patients require dialysis during acute phase. Some of them recover a normal renal function.

  2. b)

    Rapidly progressive glomerulonephritis must be identifed promptly because without specific treatment, patients lose renal function quickly and sometime die from pulmonary haemorrhage. The common manifestation is the rapid deterioration of kidney function with a nephrotic range proteinuria. Treatment depends on the type of rapidly progressive glomerulonephritis and prognosis of the disease.

  3. c)

    Thrombotic microangiopathy are acute syndromes with microangiopathic haemolytic uraemia, thrombocytopenia and organ injury. This includes thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. Platelets count is the fundamental abnormality, with haemolytic manifestations being in the forefront.

Hypertension-MOD: a peculiar hypertensive emergency

The concept of hypertensive emergency has become popular in the past years because it proposes a pragmatic approach of acute hypertension.23 However, this definition includes very different presentations such as aortic dissection, acute pulmonary oedema, acute myocardial infarction, stroke, all with specific therapeutic aspects. Hypertension-MOD is one of these hypertensive emergencies but is undoubtedly a special entity. What makes this form of hypertension special and especially dangerous is the involvement of several end organs and not only one. This entity must be recognized for several reasons: The treatment at the acute phase is not only BP lowering for instance with IV calcium antagonist but must include blockers of the renin angiotensin system and often, after a progressive titration, at higher doses that usually recommended in chronic essential hypertension. These patients are at higher risk for the future and must be followed with greater attention, especially for renal function. Blockers of the renin angiotensin system are essential part in their chronic treatment.

Conclusions

The objective of a redefinition of MH, is to facilitate recognition of these true emergencies. The condition is more common than is usually perceived and would have a much worse prognosis than the usual forms of hypertension. Early recognition and management of hypertension-MOD are fundamental to any improvement in prognosis, and we feel that a more up to date expanded definition would enable recognition of these forms of hypertension which are currently overlooked in the published recommendations. Prospective evaluation of these criteria is mandatory and should involve prospective multicenter studies.

References

  1. 1

    Lip GY, Beevers M, Beevers DG . Do patients with de novo hypertension differ from patients with previously known hypertension when malignant phase hypertension occurs? Am J Hypertens 2000; 13: 934–939.

    CAS  Article  Google Scholar 

  2. 2

    Ahmed ME, Walker JM, Beevers DG, Beevers M . Lack of difference between malignant and accelerated hypertension. Br Med J (Clin Res Ed) 1986; 292: 235–237.

    CAS  Article  Google Scholar 

  3. 3

    Gonzalez R, Morales E, Segura J, Ruilope LM, Praga M . Long-term renal survival in malignant hypertension. Nephrol Dial Transplant 2010; 25: 3266–3272.

    Article  Google Scholar 

  4. 4

    Lip GY, Beevers M, Beevers DG . Does renal function improve after diagnosis of malignant phase hypertension? J Hypertens 1997; 15: 1309–1315.

    CAS  Article  Google Scholar 

  5. 5

    Amraoui F, Van Der Hoeven NV, Van Valkengoed IG, Vogt L, Van Den Born BJ . Mortality and cardiovascular risk in patients with a history of malignant hypertension: a case-control study. J Clin Hypertens (Greenwich) 2014; 16: 122–126.

    CAS  Article  Google Scholar 

  6. 6

    Pak KJ, Hu T, Fee C, Wang R, Smith M, Bazzano LA . Acute hypertension: a systematic review and appraisal of guidelines. Ochsner J 2014; 14: 655–663.

    PubMed Central  PubMed  Google Scholar 

  7. 7

    Shantsila A, Shantsila E, Lip GY . Malignant hypertension: a rare problem or is it underdiagnosed? Curr Vasc Pharmacol 2010; 8: 775–779.

    CAS  Article  Google Scholar 

  8. 8

    van den Born BJ, Koopmans RP, Groeneveld JO, van Montfrans GA . Ethnic disparities in the incidence, presentation and complications of malignant hypertension. J Hypertens 2006; 24: 2299–2304.

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Lip GY, Beevers M, Beevers G . The failure of malignant hypertension to decline: a survey of 24 years' experience in a multiracial population in England. J Hypertens 1994; 12: 1297–1305.

    CAS  Article  Google Scholar 

  10. 10

    Lane DA, Lip GY, Beevers DG . Improving survival of malignant hypertension patients over 40 years. Am J Hypertens 2009; 22: 1199–1204.

    Article  Google Scholar 

  11. 11

    Leishman AW . Hypertension: treated and untreated; a study of 400 cases. Br Med J 1959; 1: 1361–1368.

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Lip GY, Beevers M, Beevers DG . Complications and survival of 315 patients with malignant-phase hypertension. J Hypertens 1995; 13: 915–924.

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Shantsila A, Lane DA, Beevers DG, Lip GY . Lack of impact of pulse pressure on outcomes in patients with malignant phase hypertension: the West Birmingham Malignant Hypertension study. J Hypertens 2012; 30: 974–979.

    CAS  Article  Google Scholar 

  14. 14

    Pimenta E, Calhoun DA . Hypertensive crisis: forget the numbers. J Hypertens 2012; 30: 882–883.

    CAS  Article  Google Scholar 

  15. 15

    Gosse P, Coulon P, Papaioannou G, Litalien J, Lemetayer P . Impact of malignant arterial hypertension on the heart. J Hypertens 2011; 29: 798–802.

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31: 1281–1357.

    CAS  Article  Google Scholar 

  17. 17

    Lip GY, Beevers M, Dodson PM, Beevers DG . Severe hypertension with lone bilateral papilloedema: a variant of malignant hypertension. Blood Press 1995; 4: 339–342.

    CAS  Article  Google Scholar 

  18. 18

    Amraoui F, van Montfrans GA, van den Born BJ . Value of retinal examination in hypertensive encephalopathy. J Hum Hypertens 2009; 4: 274–279.

    Google Scholar 

  19. 19

    Akoudad S, Portegies ML, Koudstaal PJ, Hofman A, van der Lugt A, Ikram MA et al. Cerebral microbleeds are associated with an increased risk of stroke: The Rotterdam Study. Circulation 2015; 132: 509–516.

    Article  Google Scholar 

  20. 20

    Griffin KA, Polichnowski A, Litbarg N, Picken MA, Venkatachalam M, Bidani AK . Critical blood pressure threshold dependence of hypertensive injury and repair in a malignant Nephrosclerosis Model. Hypertension 2014; 64: 801–807.

    CAS  Article  PubMed  Google Scholar 

  21. 21

    van den Born BJ, Honnebier UP, Koopmans RP, van Montfrans GA . Microangiopathic hemolysis and renal failure in malignant hypertension. Hypertension 2005; 45: 246–251.

    CAS  Article  Google Scholar 

  22. 22

    Shantsila A, Dwivedi G, Shantsila E, Butt M, Beevers DG, Lip GY . A comprehensive assessment of cardiac structure and function in patients with treated malignant phase hypertension: the West Birmingham Malignant Hypertension project. Int J Cardiol 2013; 167: 67–72.

    Article  Google Scholar 

  23. 23

    van den Born BJ, Beutler JJ, Gaillard CA, de Gooijer A, van den Meiracker AH, Kroon AA . Dutch guideline for the management of hypertensive crisis–2010 revision. Neth J Med 2011; 69: 248–255.

    CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to P Gosse.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cremer, A., Amraoui, F., Lip, G. et al. From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency. J Hum Hypertens 30, 463–466 (2016). https://doi.org/10.1038/jhh.2015.112

Download citation

Further reading

Search

Quick links