Endomyocardial fibrosis (EMF) is a disease that is characterized by fibrosis of the apical endocardium of the right ventricle (RV), left ventricle (LV), or both. The clinical manifestations are largely related to the consequences of restrictive ventricular filling, including left and right sided heart failure. The heart failure is associated with atrioventricular-valve regurgitation. Endomyocardial fibrosis is a major cause of illness and death in areas where it is endemic, and in its severest form carries a very poor prognosis, with an estimated survival of 2 years after diagnosis.

1. ENDOMYOCARDIAL FIBROSIS
(Davies' disease)
DR VISHWANATH HESARUR
SENIOR RESIDENT
DEPT OF CARDIOLOGY
JNMC, BELGAUM.

2. INTRODUCTION
 Endomyocardial fibrosis (EMF) is a disease that is
characterized by fibrosis of the apical endocardium of the
right ventricle (RV), left ventricle (LV), or both.
 The clinical manifestations are largely related to the
consequences of restrictive ventricular filling, including
left and right sided heart failure.
 The heart failure is associated with atrioventricular-valve
regurgitation.
 Endomyocardial fibrosis is a major cause of illness and
death in areas where it is endemic, and in its severest form
carries a very poor prognosis, with an estimated survival of
2 years after diagnosis.

3. HISTORY
 1946: Bedford and Konstam described a form of heart
disease in 40 West African soldiers -post-mortem revealed
subendocardial fibrosis with features that are now
associated with EMF.
 1946: Davies JN first coined the term EMF and said that “he
became convinced rightly or wrongly that he had met a
new disease”.
 1938 : Arthur Williams had described two cases of mitral
incompetence and correlated with large patches of fibrosis
affecting the ventricular walls at necropsy

4.  1946 : Davies did his MD thesis on this disease where he
described the pathological features as a distinct entity.
 1948 : Bedford encouraged davies to publish his observations and
Arthur Williams and JD Ball were his co-authors.
 Later, JD Ball, with his missionary job joined Christian Medial
College Vellore in India and identified the pathological
specimens at autopsy which he shipped to Davies for
confirmation.
Thus, the disease was reported from India for the first time
 1954 : Davies described the classical four pathological features of
EMF and its distribution in Africa.
Right and left ventricular endocardial fibrosis, affecting the apex
and inflow region with atrioventricular valve regurgitations
The disease came to be known as the Davies’ disease.

5.  1960 : Samuel and Anklesaria published this initial autopsy
series from south India.
 1962 : CK Gopi from Trivandrum, described the specimen
kept in the hospital autopsied in 1950s as a case of right
ventricular endomyocardial fibrosis with right atrial
thrombi.

6. EPIDEMIOLOGY
 EMF is a disorder found typically in tropical and
subtropical Africa, notably in Uganda, Nigeria, and
Mozambique
 Major cause of morbidity and mortality, accounting for
25% of cases of congestive heart failure and death in
equatorial Africa.
 A population-based study in rural Mozambique revealed a
prevalence of the disorder affecting 19.8% of the
population.

7.  The disease is increasingly recognized in other tropical and
subtropical regions within 15 degrees of the equator,
including India, Brazil, Colombia, and Sri Lanka.

8.  Increased incidence among individuals of low socioeconomic status.
 Male preponderance, is most common in children and young
adults, but has been described in individuals into the sixth decade of
life .

9. ETIOLOGY
 The cause of the underlying fibrotic process of EMF is largely
unknown; however, several theories exist and are briefly
reviewed
Eosinophilia
 Most commonly cited etiologic link in EMF.
 In support - observed that EMF resembles a late stage of
Loeffler's endocarditis (eosinophilic myocarditis) , a process
known to result from sustained eosinophilia in patients with
hypereosinophilic syndrome .
 EMF and intraventricular thrombosis have also been observed
following a variety of other eosinophilic syndromes including
hypersensitivity myocarditis , parasitic infections , eosinophilic
leukemia, sarcoma, carcinoma, and lymphoma .

10.  Despite the similarities between Loeffler’s endocarditis and
EMF, serum and myocardial eosinophilia have not been
consistently demonstrated in EMF.
 one study from Uganda found - 60 % of patients with EMF
had at least mild eosinophilia at the time of diagnosis
compared to 10 % of controls , in Kerala, India, most with
EMF did not have active eosinophilia at the time of
diagnosis.
 Endomyocardial biopsies have not demonstrated
eosinophilia in EMF, even in those suspected to have early
disease .

11. Infectious
 Several infections - toxoplasmosis , rheumatic fever , malaria , and
helminthic parasites .
 A consistent association with one organism, however, has not been
demonstrated.
Environmental exposure
 Cerium, a rare earth element, has been postulated to play a role in the
pathogenesis of EMF.
 Serum levels of cerium are high in patients with EMF compared to
controls, and it is postulated that cerium is ingested from food and
contaminated soil .
 The incidence of EMF is decreasing in India, which corresponds with a
reduction in soil cerium that has occurred with modernization.

12. Immunologic
 The presence of anti-myosin autoantibodies has been
demonstrated in EMF; however, these antibodies can be
detected in other forms of heart disease such as Dresser’s
syndrome, rheumatic heart disease, and in patients with
post-transplant rejection.
Genetic
 A familial link has been identified in many studies;
however, it is not known whether this is due to an
environmental or genetic cause or both.

13. PATHOLOGY
 EMF affects both the right and left ventricles in
approximately 50% of patients, purely the left in 40%, and
the right ventricle alone in the remaining 10%.
 The typical gross appearance is that of a normal to slightly
enlarged heart.
 The right atrium may be dilated in proportion to the
severity of right ventricular involvement.
 The hallmark feature of the disorder is fibrotic obliteration
of the apex of the affected ventricle .

14.  The fibrosis involves the papillary muscles and chordae
tendineae, leading to atrioventricular valve distortion and
regurgitation.
 In the left ventricle, the fibrosis extends from the apex to
the posterior mitral valve leaflet, usually sparing the
anterior mitral leaflet and the ventricular outflow tract.
 Endocardial calcific deposits can be present involving
diffuse areas of the ventricle.
 The fibrotic tissue often creates a nidus for thrombus
formation, which can be extensive. Atrial thrombi also
occur.
 The process usually does not involve the epicardium, and
the coronary artery obstruction is distinctly uncommon.

15. End-stage endomyocardial disease . Apical ventricular thrombi form in damaged
endocardium, and progressive endomyocardial fibrosis entraps the chordae
tendineae, leading to mitral and sometimes tricuspid valvular incompetence.
(Courtesy Murray Resnick, MD, PhD, Brown University, Providence, RI.)

16. HISTOLOGY
Histology demonstrates marked fibrotic thickening of the endocardium (arrow), with
proliferation of fibrous tissue in the underlying myocardium, which is consistent with
endomyocardial fibrosis (Masson trichrome stain, original magnification ×50).

17. CLINICAL FEATURES
 The clinical presentation of EMF depends on the chamber
involved, the location of the fibrotic lesion and its severity.
 Davies described three phases of the disease in his
patients from Uganda.
 The initial phase is an acute carditis phase, characterized
by febrile illness and in severe cases with heart failure and
shock.
 Those who survive this acute illness, progress into a sub
acute phase followed by a chronic phase.
 Most of the patients come to clinical attention in this
chronic burnt-out phase

18. Right Ventricular Endomyocardial Fibrosis
 In pure or predominant right ventricular involvement, the
right ventricular apex is characterized by fibrous
obliteration, which may extend to involve the supporting
structures of the tricuspid valve, with ensuing tricuspid
regurgitation.
 Patients exhibit an elevated JVP, a prominent v wave with
rapid y descent, and a right-sided S3 gallop.
 There is prominent hepatomegaly with a pulsatile liver,
ascites, splenomegaly, and peripheral edema, but
pulmonary congestion is typically absent because of the
lack of left-sided involvement.

19. Left Ventricular Endomyocardial Fibrosis
 In cases of predominant left-sided disease, fibrosis involves
the ventricular apex and often the chordae tendineae or the
posterior mitral valve leaflet, producing mitral
regurgitation.
 The associated murmur may be late systolic, characteristic
of a papillary muscle dysfunction murmur, or pansystolic.
 Findings of pulmonary hypertension may be prominent,
and an S3protodiastolic gallop is frequently present.

20. Biventricular Endomyocardial Fibrosis
 Biventricular EMF is more common then either isolated
right- or left-sided disease.
 The typical clinical presentation of EMF resembles right
ventricular EMF; however, a murmur of mitral
regurgitation is indicative of left-sided involvement.
 Unless left ventricular involvement is extensive, severe
pulmonary hypertension is absent and the right-sided
findings are the predominant mode of presentation.
 Approximately 15% of patients will experience systemic
embolization, and only 2% will have infective endocarditis.

22.  In a study conducted in india which included 145 pts with EMF
show clinical profile
 The mean (SD) age of the patients at first presentation was 26±3
(14±1) years for women (n = 70) and 21±1 (11±9) years for men (n
= 75); 33.1% were under 15.
Gupta PN, Valiathan MS, Balakrishnan KG,
Kartha CC, Ghosh MK. Clinical course of
endomyocardial fibrosis. Br Heart
J. 1989;62:450–4.
Sree
Chitra Tirunal Institute for Medical
Sciences and Technology,
Trivandrum 69501 1, Kerala, Indi

23. A COMPARISON OF THE CLINICAL AND CARDIOLOGICAL
FEATURES OF ENDOMYOCARDIAL DISEASE IN
TEMPERATE AND TROPICAL REGIONS
J. DAVIES ,G. VIJAYARAGHAVAN et al A comparison of the clinical and cardiological
features of endomyocardial disease in
temperate and tropical regions,1983.

24. J. DAVIES ,G. VIJAYARAGHAVAN et al A comparison of the
clinical and cardiological features of endomyocardial disease in
temperate and tropical regions,1983.

25. RV EMF
 Right atrial (RA) abnormality - peaking and increased P wave
amplitude in lead II
Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J
Pacing Electrophysiol.2011;11:129–33
ECG
DIAGNOSIS

26.  QR pattern with a diminutive R wave in lead V1 , attributed to RA
enlargement, though this pattern is seen even in patients with atrial
fibrillation (AF) .
Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J
Pacing Electrophysiol.2011;11:129–33

27.  In isolated RV EMF - A dominant R wave in V2 in the absence of QR
pattern in V1 in 14 of 25 patients resulting in early transition from a
dominant S wave in right sided chest leads to dominant R wave in V2 or
earlier .
Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J
Pacing Electrophysiol.2011;11:129–33

28.  AF is seen in the end stage patients with advanced
RV EMF.
 It is noteworthy that patients with RV EMF and AF
rarely have fast ventricular response, in striking
contrast to patients with AF and LV EMF.
 Patients with large pericardial effusion often have
low voltage QRS, satisfying the low voltage ECG
criteria.

29. LV EMF
 LA abnormality.
 AF occurs in advanced and uncorrected case of LVEMF.
 The odd finding is a uniform ST segment depression and T
wave inversion more evident in the lateral chest leads,
similar to apical hypertrophic cardiomyopathy (HCM) and
non- ST elevation acute coronary syndromes

30. Tharakan J. Electrocardiogram in endomyocardial fibrosis. Indian J
Pacing Electrophysiol.2011;11:129–33

31.  More than 50% patients with EMF have biventricular
involvement
 The ECG reflects a combination of these abnormalities.
 ECG findings reported by Balakrishnan et al from Sree
Chitra Tirunal Institute for Medical Sciences and
Technology, Trivandrum - 210 patients
 AF (33%), junctional rhythm or heart block (4.4%), right
axis deviation (29%), intra ventricular conduction
abnormality (16%) and atrial tachycardia or atrial
flutter(3.5%).
Balakrishnan KG, et al. Clinical course of patients in Kerala. In: Valiathan MS,
editor.Endomyocardial fibrosis. Oxford University Press; 1993

32.  Earlier three large studies of 60 patients, 95 patients
and 50 patients, reported AF in 40%, junctional
rhythm in 2%, RA enlargement in 32% and QR pattern
in V1 in 25% patients .
 LA enlargement was common in patients with LVEMF
and 18% of LVEMF patients had LVH (left ventricular
hypertrophy) with strain .
Sapru RP. Clinical profile of endomyocardial fibrosis. In: Sapru RP,
editor. Endomyocardial fibrosis in India. ICMR; 1983.
Vijayaraghavan G, et al. Endomyocardial fibrosis: Clinical, ECG and
radiological features. In: Sapru RP, editor. Endomyocardial fibrosis in
India. ICMR; 1983.
Jacob G, et al. Endomyocardial fibrosis in Kerala. In: Sapru RP,
editor. Endomyocardial fibrosis in India. ICMR; 1983.
Jacob G, et al. Endomyocardial fibrosis in Kerala. In: Sapru RP,
editor. Endomyocardial fibrosis in India. ICMR; 1983

33. Echocardiography
 Apical fibrosis of the right ventricle (RV), left ventricle (LV), or
both ventricles.
 Tethering the atrioventricular (AV) valve papillary muscles,
leading to mitral and/or tricuspid regurgitation
 Giant atrial enlargement .
 Restrictive filling pattern on Doppler recordings of mitral valve
inflow .
 Apical thrombi are often present

39.  In a study conducted in brazil - 12 pts with EMF were studied
with Doppler echocardiography with the purpose of describing
the echocardiographic features and identify the affected sites.
 The average age was 41 years (range 16 to 59 years), 2 men and 10
women.
 3 (25%) had isolated right ventricular involvement, one patient
(8%) left ventricular, 8 patients (66%) both ventricular.
 Doppler echocardiographic findings were: right atrium
enlargement (91%), right ventricle outflow dilatation (83%),
paradoxical septal motion (83%), left atrial enlargement (33%),
mitral and tricuspid valve prolapse (50%), pericardial effusion
(41%), mitral regurgitation (75%), tricuspid regurgitation
(100%), apex obliteration (50%) and a restrictive type flow
pattern (50%).
Tello r Cuan et al . Doppler echocardiography in endomyocardial fibrosis
, Brazil ,1994.

40.  In a study conducted in india which included 145 pts
with EMF ,Echocardiographic data were available in
86 patients.
 The mean (SD) left ventricular internal dimensions
in diastole and systole were 4.17 (1.19) cm and 2.9 (1.
07) cm respectively.
 Pericardial effusion was present in 35 (40.7%),
intracavitary thrombi in 11 (12.8%), and myocardial
calcification in 16 (18. 6%) patients.
Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh MK. Clinical
course of endomyocardial fibrosis. Br Heart J. 1989;62:450–4. Sree
Chitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 69501 1, Kerala, India

41.  An echocardiographic screening study in Mozambique
included echocardiographic criteria for the diagnosis and
staging of EMF
 As the natural history of EMF is not well defined, these
criteria will likely aid in defining the stages of this disease
and in determining the clinical significance of early EMF.

42. Classification of Endomyocardial
Fibrosis
 They defined major and minor criteria for the diagnosis of EMF
on the basis of features of advanced disease and pathologic
features of early stages described in postmortem studies.
 Endomyocardial fibrosis was diagnosed in the presence of two
major criteria or one major criterion associated with two minor
criteria
 Possible scores ranged from 0 to 35; cases with
 scores of 8 or less were classified as mild,
 scores of 8 to 15 as moderate,
 scores of 15 or more as severe.

43. A Population Study of Endomyocardial Fibrosis in a Rural Area of Mozambique Ana Olga Mocumbi, M.D.,
Maria Beatriz Ferreira, M.D., Ph.D., Daniel Sidi, M.D., Ph.D., and Magdi H. Yacoub, F.R.S. N Engl J Med
2008;359:43-9.

44. HEMODYNAMIC FINDINGS
 The typical haemodynamic finding on cardiac
catheterization is the dip and plateau pattern of
restrictive ventricular filling.

45.  In a study conducted in
Mozambique included 21
pts showed
 In patients with RV EMF,
RA pressure was increased
with prominent A waves,
which was also seen in the
right ventricular and
pulmonary artery pressure
tracings .
 The right ventricular
pressure tracing showed a
dip and high end-diastolic
pressure 5 mm Hg higher
than the pulmonary
diastolic pressure, and the
contour of the right
ventricular pressure
tracing was distorted .

46.  In patients with left
sided involvement, left
ventricular end-
diastolic pressure was
very high.
 A dip and plateau
pattern of the
ventricular pressure
curve present .
 Pulmonary
hypertension present
in all patients with left
and biventricular EMF

50.  In a study conducted which included 8 pts, their
hemodynamics showed
Vijayaraghavan G, Cherian G, Krishnaswami S, Sukumar IP. Left
ventricular endomyocardial fibrosis in India. Br Heart J. 1977;39:563–8

51. Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh MK. Clinical
course of endomyocardial fibrosis. Br Heart J. 1989;62:450–4. Sree
Chitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 69501 1, Kerala, India

52. Chest X-Ray
 Cardiomegaly - varying degrees from mild to severe.
 Right atrial enlargement in the patients with right-sided
involvement, left atrial enlargement in patients with left-
sided involvement, and biatrial enlargement in those with
biventricular involvement.
 Pulmonary venous congestion with left-sided involvement.
 Endocardial calcification

54. Somers K, Williams AW. Intracardiac calcification in endomyocardial
fibrosis. Br Heart J.1962;24:324–8

55. Vijayaraghavan G, Cherian G, Krishnaswami S, Sukumar IP. Left ventricular
endomyocardial fibrosis in India. Br Heart J. 1977;39:563–8

58. ANGIOGRAPHY
CHARACTERISTIC OBLITERATION OF THE APEX OF THE INVOLVED VENTRICLE(S)
WITH VARYING DEGREE OF AV VALVE REGURGITATION
Left ventricular angiogram in the RAO view showing obliteration of the apex
(arrow) in systole (top, a) and diastole (bottom, b).
Walid M. Hassan, MD, FCCP; Mohamed et al Pitfalls in Diagnosis and Clinical, Echocardiographic, and
Hemodynamic Findings in Endomyocardial Fibrosis A 25-Year Experience 2005

59. Right ventricular angiogram in the RAO view in a patient with right-sided EMF
showing complete obliteration of the apex of the right ventricle, dilated right
atrium, and severe TR. .
Walid M. Hassan, MD, FCCP; Mohamed et al Pitfalls in Diagnosis and Clinical, Echocardiographic, and
Hemodynamic Findings in Endomyocardial Fibrosis A 25-Year Experience 2005

61.  CMR imaging with
contrast demonstrates
myocardial fibrosis.
 In early disease where
there is suspicion for
active inflammation, CMR
may be useful in
identifying patients who
may benefit from steroid
therapy
Cardiovascular magnetic resonance imaging

62. CT SCAN

63. Endomyocardial Biopsy
Photomicrograph of endomyocardial biopsy specimen
showing marked thickening of the endocardium (E) with fibrosis
(hematoxylin-eosin, original × 200).

64. MANAGEMENT
Medical therapy
 Remains challenging.
 One third to one half of patients with advanced disease die
within 2 years
 Atrial fibrillation is a poor prognostic indicator, although
symptomatic relief can be achieved with rate control
 Heart failure - difficult to control, and diuretics are effective only
in early stages of disease, losing efficacy with advanced ascites.

65. Surgery
 Endomyocardial resection - endocardectomy with valve
replacement or repair - especially in subjects in advanced heart
failure
 Immediate postoperative mortality is high - 15 to 30 %.
 A surgical series of 83 patients from Brazil all in NYHA class
grade III to IV, and with a mean follow-up of 7.6 years had a
survival probability at 17 years of 55 percent .
 4 (5.8%) patients - recurrence of the fibrosis and were reoperated on
and in 6 (8.8%), EMF appeared in the other ventricle.
 5 (7.3%) patients were reoperated on to replace either a valve prosthesis
or a native valve which had been preserved during the first procedure.
 Only 24 (45%) of the 53 surviving patients are in functional class I or II.
Fernando Moraes , Cleuza et al Surgery for endomyocardial fibrosis
revisited September 1998

66.  Published series have been small, overall experience
is limited, and questions remain about the
appropriate timing, peri-operative mortality, and
long-term prognosis .

67. Left ventricular angiogram in the RAO view showing a small left ventricle
with apical obliteration,severe MR, and dilated left atrium in a patient with
left-sided EMF (top, a) and after surgery with endocardectomy
and mitral valve replacement (bottom, b).
Fernando Moraes , Cleuza et al Surgery for endomyocardial fibrosis
revisited September 1998

68. CLINICAL COURSE
 The factors significantly affecting survival were
Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh MK. Clinical
course of endomyocardial fibrosis. Br Heart J. 1989;62:450–4. Sree
Chitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 69501 1, Kerala, India

69. Gupta PN, Valiathan MS, Balakrishnan KG, Kartha CC, Ghosh MK. Clinical course of
endomyocardial fibrosis. Br Heart J. 1989;62:450–4. Sree
Chitra Tirunal Institute for Medical Sciences and Technology,
Trivandrum 69501 1, Kerala, India

70. Changing natural history of endomyocardial fibrosis
 Gupta and colleagues defined the natural history of the
disease in Kerala in the late 1980s.
 Follow up of the initial 200 patients showed a 10 year
survival of only 37 %.
 Ascites, atrial fibrillation and NYHA class IV were the poor
prognostic indicators.

71.  Eighty nine patients, who underwent endocardiectomy
with MVR had an actuarial survival of 55 % during the
same period.
 Significant decline in the number of new cases happened
in the hospital admissions in Kerala in the subsequent
decades.
 Natural history in them was more favourable with less than
10 per cent mortality on seven years follow up.
 The average number of cases seen declined by half in the
last decade, compared to the previous decade.

72.  The mean age of the patients seen is now 33 yr compared to
25 yr in the previous decade, suggesting that people who
were asymptomatic in the previous era are now being
picked up on evaluation.
 There are no patients below 10 yr, whereas in the previous
decade, 28 per cent were below the age of 15 yr.
 The patients are less symptomatic and older.
 The majority are incidentally diagnosed when evaluated for
electrocardiographic or echocardiographic abnormalities.

73.  Temporal correlates of this changing natural history are worth
analyzing.
 The period noted in the natural history studies belong to the 30 year
period of 1976 to 2007
 Kerala witnessed substantial economic, nutritional and health
transitions.
 Cassava and plantain are no longer the staple diet for the Keralites.
 The per capita calorie consumption increased from 1600 to 2100 Kcals.
 The nutritional deficiency disorders were replaced by those of over
nutrition and currently, Kerala is the diabetic capital for India.
 Thanks to the good female literacy, health status of Kerala is acclaimed
as an example for good health at low cost.

74.  A community survey shows that there is a substantial decline in
worm load per child.
 Filarial endemicity continues to be little less, with rigorous
governmental programmes initiated for its control.
 Eosinophilia in children is now uncommon.
 There is substantial decline in rheumatic fever and rheumatic
heart disease in children of Kerala correlating with the improved
health care services and quality of life.
 The question which needs to be answered now is what really
caused this decline; is it the change in living standards, or
change in the dietary pattern or the reduction in childhood
infections? By and large, endomyocardial fibrosis could be a
reaction pattern of the endocardium to a variety of insults

75.  Presence of interstitial fibrosis, myohypertrophy, and calcification
speaks of the role of cytokines in its genesis.
 Predominant right ventricular involvement in children could indicate
an insult when the right ventricle could be more susceptible.
 Right ventricle receives most of the umbilical venous return in utero
and is more dominant.
 But no antenatal cases are reported till date and the youngest report is
that of a 4 month old baby.
 The inflammatory response occurring in the younger age group could
manifest as calcification in later years.
 Whether this calcification has its similarity to vascular and valvar
calcium occurring in older age group; if so, could it be the factor which
holds the key for unraveling this mystery?

76. SUMMARY
 EMF is a restrictive cardiomyopathy observed in the tropics usually at
the end-stage of the disease.
 It may be indistinguishable from Loeffler’s endocarditis, observed in
temperate climates.
 The pathogenesis remains unknown; however, eosinophilia may play a
role.
 Echocardiography may show uni- or bilateral ventricular apex
obliteration with severely dilated atria and a restrictive filling pattern.
 The prognosis is poor, with a mortality estimated at 25 % per year.
 Surgical treatment with endomyocardial resection and valve
replacement may be beneficial in patients with advanced apical
obliteration and sever heart failure symptoms.