Patho- Reproduction-Bloooood--Renal

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1

Total blood volume

Women:

Men:

75.5 ml/kg

66.5 ml/kg

2

How many liters of blood in an adult body?

6-7 L

3

Blood cells make up what percentage of blood

45

4

Plasma makes up what percentage of blood

55

5

Plasma is ____ water and ____ plasma proteins

93%

7%

6

3 types of plasma proteins

serum albumin

fibrinogen

serum globulin

7

Inorgranic constituents of blood

Iron

electrolytes

8

RBC count

4.2-6.2 mil cells/mm3

9

Aplastic anemia is a

stem cell disorder

10

how is aplastic anemia catergorized

-a lack of hematopoietic tissue

-fatty marrow replacement

-pancytopenia

11

Aplastic anemia

HGB

low

12

Aplastic anemia

HCT

Low

13

Aplastic anemia

mean corpuscular volume (MCV)

normal

14

Aplastic anemia

mean corpuscular hemoglobin concentration (MCHC)

low

15

Aplastic anemia

Mean corpuscular hemoglobin (MCH)

low

16

Aplastic anemia

reticulocytes

low

17

Aplastic anemia

RBC, RBC, platelets

low

18

Adaptations to anemia include

-increased HR

-increased CO

-preferential blood flor to critical organs

-increased circulatory rate

19

How does the body compensate for aplastic anemia in the long term?

increased erythropoietin

20

Symptoms of severe anemia

-tachycardia

-pallor

-hypotension

-transient murmurs

-angina

-night cramps in muscles

-tinnitus/roaring

-claudication

-HA

21

Aplastic anemia is anemia related to

decreased RBC production

22

Aplastic anemia due to decreased functional bone marrow mass is usually the result of

-toxic injury to bone marrow stem cells

-radiant injury to bone marrow stem cells

-immunologic injury to bone marrow stem cells

23

Two classifications of aplastic anemia

-acquired

-familial

24

Acquired aplastic anemia can be caused by which viruses?

-epstein barr

-HIV

-hepatitis

-dengue

25

Pregnancy can cause

Aplastic anemia

26

What genetic issue can cause aplastic anemia?

putative hereditary uptake of folate

27

Aplastic anemia usually effects people ages

15-25 and over 60

28

Signs of clotting disorder can be evidence of _________- anemia

aplastic

29

Aplastic anemia is fatal unless

managed with bone marrow transplantation

30

Why does renal failure lead to aplastic anemia?

primarily--failure of renal endocrine function--erythropoietin

Secondary--failure of excretory function--hemolysis, bone marrow cell depression, blood loss

31

Renal failure anemia usually involves which labs

low HGB, HCT, RBC

Normal WBC, platelet, leukocyte, corpuscular labs

32

At what hematocrit do symptoms of anemia usually appear?

<20%

33

Target hemoglobin level

11--12 g/dl

34

HGB greater than 12 g/dl is associated with

thromboembolic events

35

What happens when pts have low B12?

Megaloblastic madness

36

Hemolytic disease of the newborn is anemia related to

extrinsic red cell destruction

37

ABO incompatability is the most common cause of hemolytic disease of the newborn, but __________-

Rh is more important because of its association with severity

38

Lab features of hemolytic disease of the newborn

-increased reticulocytes

-nucleated RBCs in peripheral blood

-bilirubin reflects severity of disease (ability to excrete)

39

Clinical manifestations of hemolytic disease of the newborn

-hemolytic anemia

-diffuse extravascular coagulation

-extra medullary erythropoietin

-hyperbilirubinemia/jaundice

-petechial hemorrhages

-hepatomegaly/splenomegaly

-HF

-kernicterus

40

newborn condition marked by several neuro symptoms associated with high blood nilirubin

kernicterus

41

hemolytic disease of the newborn often results in

death before birth

42

Primary amenorrhea is

failure to begin menstruation by age 16

43

Secondary amenorrhea is

cessation of established menstruation for 3 or more periods

44

The initial rise in FSH and LH in the menstrual cycle results from

a decline in progesterone and estrogen

45

An increase in progesterone and estrogen is caused by

action of gonadotropic hormones (LH/FSH)

46

Endometrium proliferates again in response to

estrogen

47

uterine bleeding outside of menstruation

metrorrhagia

48

debilitating increase in the amount or duration of menstrual bleeding

menorrhagia

49

Absent or diminished progesterone levels results in

thick, highly vascular endometrium lacking structural support--Unopposed estrogen

(results in spontaneous superficial bleeding)

50

Symptoms of dysmenorrhea tend to __________ with age

decrease

51

Childbirth permanently decreases symptoms of dysmenorrhea---T or F?

False

52

What causes primary dysmenorrhea?

increased prostaglandins (hormone-like fatty acids) released from the endometrium have profound effects on smooth muscle and vasomotor tone

53

Ibuprofen, naproxen and celecoxib treat dysmenorrhea because

they are prostaglandin synthetase inhibitors

54

prostaglandin development in dysmenorrhea requires

high estrogen-low progesterone in proliferative phase

55

What type of neoplasms can cause amenorrhea?

adrenal

pituitary

ovarian

56

Infrequent menstruation is called

oligomenorrhea

57

Light menstruation is called

hypomenorrhea

58

secondary dysmenorrhea is typically

dull pain that increases with age

59

Primary dysmenorrhea is

sharp suprapubic pain that limits activity

60

Two failures required for uterine prolapse

-supportive structures

-vaginal wall

61

A small supportive device used to hold the uterus in place

pessary

62

5 uterine retrodisplacement positions

-anteverted

-midposition

-anteflexed

-retroflexed

-retroverted

63

protrusion of the bladder into a weak part of the vaginal wall

cystocele

64

ANY acute, subacute, recurrent or chronic infection of the oviducts and ovaries with involvement of the adjascent reproductive organs

PID

65

Infection of the oviducts

salpingitis

66

When connective tissue between reproductive organs is involved in PID it is called

parametritis

67

PID can result in

Infertility

ectopic pregnancy

chronic pelvic pain

68

In healthy, non-PID women, cervical secretions provide a

bacteriostatic barrier

69

PID may result from-

infection during or after pregnancy

IUD insertion

abortion

pelvic surgery

--Bloodborne

-pelvic abscess

-diverticulitis

-ruptured appendix

70

Gonorrhea and chlamydia readily break the

cervical barrier--> cause PID

71

During parturition, the traumatized endometrium favors

multiplication of bacteria

72

PID generally presents with

Tenderness on palpation

-adnexa

-fever

-high WBC (>10,000)

--purulent vaginal discharge

73

When is PID life threatening?

If a pelvic abscess ruptures

74

Inflammation of the vulva/vagina

vulvovaginitis

75

Why does candidiasis vilvovaginitis get worse or show up during the secretory phase of the menstrual cycle and when exogenous estrogen is used?

fungus likes sugar, glycogen levels rise in the vaginal environment

76

Which viruses can cause vulvovaginitis?

HPV/ HSV

77

Normal vaginal pH

<4.5

78

Uterine leiomyomas are also called

fibroids

(most common aberrant growths)

79

Fibroids effect ______ women 3x more than ________-

black

white women

80

____ appear to be major factors in the growth of fibroids, but the actual cause is _______-

age, estrogen, and growth hormone

unknown

81

Endometrial tissue outside of the uterus

endometriosis

82

Oral contraceptives treat ovarian cysts by

preventing ovulation

83

Risk factors for endometriosis

30-40 yrs old

never given birth

84

Infertility rate for women with endometriosis

30%

85

Theories about endometriosis

-metaplasia

-transportation (backwards flow of tissue)

-induction (BOTH^^)

86

MAIN cause of cervical cancer

HPV

87

Lesser causes of cervical cancer

-sex at a young age or with multiple partners

-STDs

-several pregnancies

88

PAPs for cancer should be started at age ____ and done every _____ after _____ consecutive negative PAPS after age 30

21

2-3 years

3

89

PAPs can be stopped for low risk women after age

70

90

Abnormal cells may be present in cervical epithelium for ______ before cancer develops

10 years

91

Early signs of cervical cancer

-abnormal bleeding

-pain and bleeding after sex

-abnormal discharge

92

95% of all cervical cancer is

Squamous cell carcinoma

93

5% of all cervical cancer is

adenocarcinoma

94

Cervical precancer treatment

-cryotherapy

-excision

-laser therapy

95

Cervical cancer treatment

-hysterectomy

-radiation

-chemo

96

Radical surgery for advanced cervical cancer involving removal of all pelvic organs is called

pelvic extenteration

97

5 year survival for cervical cancer

stage 1--

stage 4--

93%

15%

98

Gardasil protects against which types of HPV

6

11

16

18

99

HPV 6,11, 16 & 18 are responsible for

70% of all cervical cancers

90% of all genital warts

100

Lesser known HPV vaccine __________- protects against ___ & ____

Cervarix

16 & 18

101

Which HPV vaccine is suggested for tween girls/boys (9-12, 26 at latest)

Gardasil 9

102

Cancer uncommon to young women, but found in equal rates to cervical cancer after menopause--

Endometrial

103

Related factors to endometrial cancer

-infertility

-estrogen use

-late (>55) menopause

-obesity/HTN/diabetes

104

THE most common symptoms of endometrial cancer is

-bleeding between periods

-postmenopausal bleeding

105

Endometrial cancer 5 year survival rate

stage 1--

metastasized--

90%

17%

106

Which female cancer has replaced cervical cancer as the leading cause of death and why?

ovarian

asymptomatic until too late

45% 5 year survival

107

Symptoms of later stage ovarian cancer

-increased abdominal girth

-weight loss

-pain

-dysuria/frequency

-constipation

108

Which genes put a woman at greater risk of ovarian cancer?

BRCA1/2

109

Which med puts baby girls in utero at risk of vaginal cancer?

diethylstilbestrol

110

Vulvar cancer risk factors

-chronic pruritus w/ dryness/swelling

-obesity/HTN/diabetes

-never pregnant

111

What tissue change may precipitate vulvar cancer?

Leukoplakic changes (whitish plaques or ulcerated lesions)

112

Once vulvar cancer develops, what may be present

-masses

-abdominal defecation/urination

113

Pregnancy induced HTN is characterized by

increased arterial pressure

proteinuria

salt and water retention by kidneys

weight gain

Edema

114

HTN complicates _____ of all births

5-8%

115

Who is at risk of developing pregnancy induced HTN?

teens and 30s-40s

multiple fetuses

renal/cardiovascular disease

HTN/Diabetes

116

What happens to the kidneys in pregnancy induced HTN?

thickening of glomerular tufts-- fibrinoid deposits in basement membrane

117

Arterial spasms occur where in pregnancy induced HTN?

brain

liver

kidneys

118

Is it normal for renal blood flow and glomerular filtration to decrease during pregnancy?

No, but it happens in pregnancy induced HTN

119

Severe cases of pregnancy induced HTN result in

-EXTREME vascular spasticity throughout body

-clonic convulsions

-coma

-renal failure

-hepatic malfunction

-extreme HTN

120

Severe pregnancy induced HTN usually occurs when

shortly before birth

121

Why is fatality from pregnancy induced HTN less than 1%?

-vasodilators

-quick delivery

-seizure prophylaxis

-

122

The most common form of cancer in women between 25 and 75

breast

123

Breast cancer risk factors

-radiation

-dietary factors

-lack of access to health care

-reproductive and hormonal factors

-reproductive factors

-family hx

124

Breast cancer

hormonal factors

menstruation before 12

menopause after 55

40 years of menstruation or more = 2x risk in 30 yrs or less

--HRT progesterone and estrogen

125

Breast cancer

reproductive factors

lower risk if give birth under 18 and/or lots of kids

higher risk if give birth after 35 and/or few kids

126

Breast cancer

dietary

unknown, but maybe dietary fat increases risk?

127

Other than prophylactic surgery, what may be done to prevent

Breast cancer in high risk women?

chemoprevention

selective estrogen receptor modulators

128

Breast cancer

age factors

25 and older, increasing with age

129

Sketchy Breast cancer lump?

painless, hard, poorly movable

130

When are professional breast exams suggested?

after 40

131

half of malignant breast tumors are found where

upper quadrant

132

Other sketch breast cancer signs in breast

dimpling, change in contour

bloody discharge

nipple retraction

133

Where are most breast cancers found?

glandular epithelium of ducts

134

Where does breast cancer commonly metastasize to?

liver

lung

bones

135

Breast cancer is usually

carcinoma

136

Breast cancer 5 year survival

no lymph involvement-

lymph involvement-

mets-

98%

85%

25%

137

Removal of breast and some axillary lymph

modified radical mastectomy

138

Removal of breast, axillary lymph, and pectorals

radical mastectomy

139

Why are SERMS used to help treat breast cancer?

The malignant cells have cytoplasmic hormone receptors that promote division and growth

140

What is syphilis?

systemic vascular infection

141

Stages of syphilis

-incubation

-primary

-secondary

-latent

-late (tertiary)

142

What bacteria causes syphilis?

Treponema Pallidum

anaerobic spirochete

143

What does syphilis infect?

abraded skin or mucous membranes

144

Syphilis spreads to multiple organ system within

hours

145

How long is the syphilis incubation period?

30-90 days

146

The primary stage of syphilis manifests with

a chancre, a painless, ulcerative lesion at port of entry

147

Why does syphilis take until the latent phase to be diagnosed in females?

the primary chance occurs in the vagina or on the cervix

148

Where can a primary stage syphilis lesion erupt?

-eyelids

-fingers

-anus

-penis

-lips/tongue

-nipples

149

What happens in the secondary stage of syphilis?

the chancre resolves within 3-6 weeks and becomes fever, malaise, lymphadenopathy, and a mucosal or cutaneous rash

(it is in the blood and lymph)

150

What initiates the latent stage of syphilis?

resolution of fever/malaise/rash/lymphadenopathy/rash

151

How long can latent syphilis last?

40 years

152

What percentage of patients even experience the late (tertiary) stage of syphilis?

1/3

153

What systems are especially vulnerable to late syphilis?

Nervous and cardiovascular

154

Cardiovascular effects of late syphilis?

aortic stenosis

155

Neuro effects of late syphilis?

paresis

blindness

mental deterioration

156

Why can treatment of syphilitic pregnant women before week 15 prevent damage to the fetus?

an inflammatory response to the pathogen does not occur until then

157

Syphilis in utero can cause

physical deformities and developmental disabilities

158

Syphilis is treated with

Benzathine Penicillin G

doxy/tetracycline

159

Treated syphilis is continually assessed for __ months

24

160

Gonorrhea infects the ___________ and causes a patchy inflammatory response in the

columnar epithelium

submucosa

161

Gonorrhea is usually asymptomatic in women, but it may present with

purulent discharge

dysuria

vaginal bleeding

162

Gonorrhea usually effects which parts of women

-Bartholin and skene glands

-cervix

urethra

anus

163

What age groups (female) have the highest rates of Gonorrhea?

Males/

15-24

20-24

164

Signs of Gonorrhea in males

-dysuria

-purulent discharge

-urethritis

-redness and swelling at infection site

165

Symptoms of Gonorrhea usually occur after a

3-6 day incubation

166

Gonorrhea MAY cause

inflammation of the

-larynx

-conjunctivae

-anus

167

Gonorrhea extends its infection via the

lymphatic system

168

Gonorrhea extension infection occurs in what areas?

Men

women

oviducts (scarring and fibrosis can result in infertility)

epididymis

169

What causes chlamydia

C trachomatis

170

Upper reproductive tract infection with chlamydia is an important cause of

PID

ectopic pregnancy

infertility

171

Which is less symptomatic? Chlamydia or gonorrhea

Chlamydia

172

What can happen if a woman has chlamydia during childbirth?

ophthalmia neonatorum

173

Why is treating chlamydia and gonorrhea difficult

bacterial resistance

174

Kidney pain is often referred to as

CVA (costovertebral angle) tenderness

T10-L1

175

Kidney pain often radiates to

labia

scrotum

176

Urine thickness is called

turbidity

177

Alterations in structure and function of glomerular capillaries

glomerular disorders

178

3 layers of glomerular capillaries --- filtration barrier

endothelium

basement membranes

podocytes (footlike projections)

179

When filtrate passes through slit pores between podocytes, it

enters the bowman capsule and then moves into the proximal tubule

180

__________ tubule to __________ tubule

distal

proximal

181

When there is excessive protein loss over time,

nephrotic syndrome

182

What qualifies as excessive protein loss

3-3.5g in 24 hrs (100 mg is normal)

183

Nephrotic syndrome requires

leaky and inflamed glomerulus

184

Common causes of nephrotic syndrome

minimal change disease

focal segmental glomerulosclerosis

membranous nephropathy

any injury to glomerulus to allow protein loss

185

What exactly is injured in nephrotic syndrome?

basement membrane and slit pores that normally block protein filtration

186

Pyelonephritis is unlikely to occur unless

urine reflux

obstruction

ascending infections

diabetes

187

Pregnant women are at risk for pyelonephritis because of

anatomical changes to urinary tract

188

Who is most at risk for pyelonephritis?

babies

elderly

young women

189

ACUTE pyelonephritis usually occurs as a result of

ascending infection

190

In acute pyelonephritis, what is responsible for tubule damage?

bacterial toxins

inflammatory response

191

Chronic kidney disease progresses more quickly after

pyelonephritis

192

Decreased renal function after acute pyelonephritis occurs in about

3-4% of cases

193

When organisms in the bloodstream originate from urinary infection

urosepsis

194

What % of sepsis cases are from UTIs?

20-30%

195

What urinalysis finding differentiates pyelonephritis from UTI?

WBC casts because they are formed in the kidney tubules

196

atrophied, scarred kidneys with blunting of calices secondary to infection

chronic pyelonephritis

197

typical cause of chronic pyelonephritis

refluxed infected urine

198

Findings in chronic pyelonephritis

small

parenchymal scarring

caliceal deformity

chronic inflammation

199

Risk factors for chronic pyelonephritis

-obstructive (renal calculi)

-neurogenic bladder

-vesicoureteral reflux

-underlying intrarenal disease

200

Diagnosis chronic pyelonephritis requires ultrasound or imaging because

urinalysis results will not be as profound

201

Glomerulonephritis involves

an assortment of immune mediated conditions that involve inflammation of the glomeruli

202

Primary glomerulonephritis is

autoimmune

203

Secondary glomerulonephritis is

-matabolic

-malignant

-infectious systemic

-autoimmune

204

Signs of acute glomerulonephritis

-proteinuria

-hematuria

-oliguria

-azotemia (nitrogen wastes)

-edema

-htn

205

Postinfectious acute glomerulonephritis is usually the result of

skin or throat strep B

viruses

206

Postinfectious glomerulonephritis usually occurs

1-3 wks after initial infection

207

The key to glomerulonephritis

antibody deposition leading to inflammation

208

After immune complex deposition in glomerulonephritis, what happens

Mesangial cells proliferate, resulting in proliferative lesions--> complements system and immune cells-->lysosomal enzymes attack glomerular walls

209

The immune mediated structural changes in glomerulonephritis reduces

surface area for filtration, allowing substances to pass into glomerular space

210

Why does GFR decrease in glomerulonephritis?

angiotensin II and leukotrienes contract mesangial cells and reduce perfusion to glomerular capillaries

211

IGA nephropathy (berger syndrome) is

the most common type or primary glomerularnephritis

212

Rapidly progressive glomerulonephritis is also called,

crescentis, because of crescent shaped lesions

213

Goodpasture syndrome is

acute glomerulonephritis with pulmonary alveolar hemorrhage and anti-glomerular basement membrane antibodies

214

Nephrotic syndrome manifestations

-propensity for thrombus formation

-hypoalbuminemia

-hyperlipidemia

-generalized edema

215

Why does hypoalbuminemia cause hyperlipidemia and increased thrombus?

the liver is stimulated to produce lipoproteins and clotting factors

216

Causes of nephrotic syndrome

-DIABETES

-lupus

-malignancies

-infections

-vasculitis

217

How common is nephrolithiasis?

10-15% of americans will have them

(especially white folsk)

218

High temperatures and sedentary work are associated with

kidney stones

219

Kidney stones are common in age

20-30

220

Most common type of kidney stone

calcium oxalate

221

What causes calcium oxalate stones?

-genetics

-hypercalcemia

-increased GI absorption

-prolonged immobility

-shitty renal resorption

222

What causes struvite stones?

UTI with urea splitting bacteria (pseudomonas, proteas, kliebsella)

urinary stasis

223

What causes uric acid stones?

obesity

diabetes

hyperuricosuria

224

Medication induced kidney stones

Triamterene

Guafenesin

indinavir

xanthene

225

Renal colic

associated with stones, intermittent, spasmodic sharp pain

226

Stone pain is intense, causing __________ until _______

tachycardia, tachypnea, diaphoresis, vomiting

it reaches the bladder

227

How to diagnoses kidney stones

CT

228

Stones will pass if they are less than _________-

surgery is needed if they are _________

5mm

7mm

229

Dietary changes to avoid kidney stones

avoid fish, poultry, meat

avoid coffee tea colas (<2 per day)

less calcium/more Vit D

limit sodium and oxylate

avoid high purine for uric acid stones

increased fluids (2L plus)

230

Kidneys that do not work well enough to keep protein will also

spill fluid into tissues

231

GFR in kidney failure

<60 for 3 months

232

Signs of kidney failure

-HTN

-high urea

-high creatinine

233

What electrolytes are retained in chronic kidney disease?

Potassium

phosphorus

magnesium

234

Which drugs can prevent proteinuria?

ACE inhibitors

angiotensin 2 blockers (preferred)

235

BP goal in chronic kidney disease

130/80

236

When is metabolic acidosis due to chronic kidney disease not worth treating?

>7.30

237

When does hyperkalemia need to be treated?

>6

(admin calcium gluconate, DW5, and insulin)

238

Calcium loss is a concern with

chronic kidney disease (PTH needs to be suppressed)

239

Because of protein loss in kidney failure,

fat and carbs have to make up for it

240

Dietary restrictions for chronic kidney failure

-sodium

-potassium

-phosphorus

-potassium

-protein

-maybe fluods

241

In chronic kidney failure, __________ system is also at risk

cardiovascular

242

Drugs to treat ___________ are a huge concern for pts with kidney failure

depression

243

What are the biggest reasons for the use of dialysis

-hyperkalemia

-uremia

244

Acute tubular necrosis is

intrinsic acute kidney injury

245

Two types of acute tubular necrosis

nephrotoxic

ischemic

246

the most common cause of acute tubular necrossi

sepsis

247

Tubules can repair themselves in 10-20 days IF

the basement membrane is intact

248

The micturition center is in the

pons

249

Normal amount of residual urine

50-100 ml

250

Stress incontinence is caused by

intraabdominal pressure

251

cause of overflow incontinence

underactive detrusor muscle

urethral obstruction

252

Transient incontinence is typically due to

bowel obstruction, infection, impaction,

253

Urge incontinence can be treated through

pelvic floor exercises

254

Primary nocturnal enuresis

toddleys

255

secondary enuresis

after 6 months of dryness

256

monosymptomatic nocturnal incontinence

child with incontinence and no other urinary symptoms

(should test for diabetes)

257

nonmonosymptomatic nocturnal incontinence

child has other symptoms, like urgency, frequency

258

pATHOGENESIS of enuresis

vasopressin deficiency

overactivity of detrusor

familial

immature/abnormal arousal mechanisms

259

Treatments for enuresis

treat constipation

anticholinergics

imipramine

desmopressin

260

The pons does what for urination

relaxes the internal sphincter

contracts the bladder

261

Sympathetic innervation of the bladder mostly controls

blood flow and pain

262

parasympathetic innervation of tha bladder from S2-S4 register

stretch of the bladder

motor nerves stimulate reflex detrusor contraction

263

vesicouretal reflux is mainly due to incompetence of

the valve at the bladder-ureter junction

(shortened ureteral tunnel)

264

vesicoureteral reflux can cause

HTN

pyleonephritis

renal scarring

renal insufficiency

265

Interstitial cystitis is also called

bladder pain syndrome

266

to qualify as interstitial cystitis, what must be present

at least 6 months of bladder pain and at least one lower urinary tract symptom

267

Interstitial cystitis pain is often relieved by:

worsened by:

voiding

booze, caffeine, peppers & citrus

268

"Classic" interstitial cystitis is characterized by ______ but it is only found in ____% of cases

visible, inflammatory lesions of bladder mucosa called hunner ulcers

10

269

Interstitial cystitis is found in 5 times more ___________

women than men

270

Interstitial cystitis pathophysiology is unknown, but it seems to involve

shitty urothelium (maybe abnormal glycosaminoglycan layer leading to lack of protective layer)-->increased permeability, absorption of harmful urine components

271

Other than shitty epithelium, what may contribute to interstitial cystitis?

sensitive afferent nerves/ silent C-fibers not being silent

maybe cytokines and shit

272

What is often comorbid in interstitial cystitis?

pain syndromes--> suggestive of neurogenic/autoimmune mechanisms