Ongoing Pelvic / Lower Abdominal Pain and a Negative Work-Up: What Next?
The Case
32 yo G2P0020, previous history of 2 SABs, regular menses, negative pregnancy test
Presents for evaluation and management of pelvic/abdominal pain
Chief Complaint
Experiencing recurring episodes of pelvic/lower abdominal pain, 8/10 intensity for days at a time
Sometimes experiences dull, aching, nonradiating, 4/10 intensity prior more acute episodes
Some relief with ibuprofen 600 mg every 6 hours
Pain is sometimes increased with bowel movements, urination, intercourse during more acute episodes
Has seen multiple specialists (Gyn/GU/GI) in the past
Ongoing problem, unresolved for at least 2 years
Has undergone laparoscopy but no diagnosis as of yet
Synopsis
The differential diagnosis of pelvic/ lower abdominal pain is extensive. Sometimes, the diagnosis is clear, but patients may present with ongoing pain, lasting several months in duration. Of particular concern is when such pain leads to functional disability, need for medical care and incomplete relief with prior medical and surgical therapies. Below, we provide key points to consider when performing the work-up as well as where to look next when a clear answer from the common differential list is not apparent.
Use of a daily diary may aid in establishing temporality and relationship to menses
Site of pain | Duration | Positional change
Association with bowel/bladder function
Ethnicity may be important (see rare causes below)
Review
Medical treatments | Surgeries
Menstrual History | Pelvic infections
Ask about
History of sexual or physical abuse
Vague abdominal symptoms can be associated with undiagnosed ovarian cancer and should not be dismissed
Note: Watch for ‘Red Flag’ signs and symptoms which require immediate evaluation/referral
Rectal bleeding
New bowel symptoms and age >50
New pain after menopause
Pelvic or abdominal mass
Suicidal ideation
Excessive and/or unintentional weight loss
Family history of inflammatory bowel disease or colorectal cancer
Abnormal vaginal bleeding, especially >40 years and postmenopausal
Postcoital bleeding
Physical
General Musculoskeletal Exam
Observe gait, pain on position change
Disorders of pelvic floor and hip muscles may present as pain on standing up or lying down
Evaluate
Spine | Paraspinous muscles | Sacroiliac joints
Abdominal Exam
Examine and palpate abdomen, both standing and reclining to assess for
Hernia | Endometrioma | Muscular trigger points
Myofascial tenderness
Carnett sign: Palpate in the presence of flexed abdominal wall muscles
Increased tenderness: Contribution from myofascial sources
Decreased tenderness: Underlying visceral sources
Standing position
Easier to detect hernias or rare abdominal wall endometrioma
Assess for pulsating masses and bruit
Pelvic Exam
Begin pelvic exam with cotton swab palpation of vulva/vestibule
Check for vulvar vestibular syndrome and vaginal trigger points (see ‘Related ObG Topics’ below)
Palpate (using single digit) to evaluate pelvic floor for tension myalgia
Levator plate | Piriformis | Obturator muscles
Palpate without abdominal hand (also initially single digit) to eliminate myofascial component
Cervix | Uterus | Adnexa | Bladder | Urethra
Add back abdominal hand to assess size/shape/mobility
Rectovaginal exam
Assess for endometriosis and rectal masses
Labs
STI screening
Offer to all sexually active women
CBC and ESR
Consider if chronic PID/infection is a consideration
CA-125
CA-125 may be elevated in women with deeply infiltrating endometriosis
Urinalysis and culture
Further urogynecologic work-up may be required in the setting of bladder/ upper urinary symptomatology or clinical findings
Imaging
Transvaginal ultrasound
Can reliably identify ovarian endometriomas, fibroids, hydrosalpinges
In skilled hands, can be as sensitive as MRI for adenomyosis
Pelvic MRI
May be useful in diagnosing adenomyosis
Can help ascertain / identify palpable nodules on pelvic and rectovaginal exam
Consider lower endoscopic ultrasound to evaluate rectal endometriosis
Role of Laparoscopy
Once considered the ‘first line’ gold standard
Evidence for immediate ‘first line’ investigation is lacking, and other investigations may be completed initially
Will usually follow a complete nonsurgical work-up
‘Conscious pain mapping’ of the pelvis (‘microlaparoscopy’), under local anesthetic to identify what organs are generating pain has been reported but not widely adopted
Laparoscopy is still an important procedure for documentation of peritoneal endometriosis and adhesions
Laparoscopy alone may underdiagnose endometriosis and biopsies of suspicious areas may be required
Minimally invasive laparoscopic surgery has an important role in diagnosis and treatment
Among well trained-surgeons, can lead to relief of pain related to endometriosis, chronic TOA or hydrosalpinx among other disorders
Part 2: Differential Diagnosis – Common Disorders
The following differential diagnosis list is not exhaustive, but represents disorders to consider in a woman with ongoing pain, a non-surgical abdomen, and negative pregnancy test
Gyn
Endometriosis and/or Adenomyosis (see ‘Related ObG Topics’ below for clinical findings, evaluation and treatment of endometriosis)
Symptoms
Do not correlate with extent of disease
Vary widely
May overlap with Irritable bowel syndrome (IBS) and interstitial cystitis
Cyclical presentation and point tenderness associated with dyspareunia suggests the possibility of nodules in the cul-de-sac
Adhesive Disease
Associated with dense, not fine adhesions
Strong data on association remains limited
History: Surgery for
PID | TOA | Endometriosis
Physical: Uterus fixed in position on examination
Imaging: Benign
Residual Ovary Syndrome (Trapped Ovary Syndrome)
Ovarian preservation or unilateral salpingo-oopherectomy in premenopausal patient following hysterectomy
Ovary can become entrapped in adhesions or attached to other tissues, such as vaginal apex
Ovarian Remnant
Residual ovary present following oophorectomy
Classic symptoms
Absence of vasomotor symptoms | Cyclic pain | Dyspareunia if attached to vaginal apex
“Renal Nutcracker syndrome”—compression of left renal vein between abdominal aorta and superior mesenteric artery
Rare cause of lower abdominal/pelvic pain with intermittent hematuria
Vaginal Apex Pain
History
Commonly presents as dyspareunia following hysterectomy
Physical
Use a cotton-tipped applicator to examine the cuff
Look for focal pain in the fornix
Temporary relief with apical local anesthesia
Musculoskeletal
Levator Pain
Pain with sitting
Worsens over the day
Associated with dyspareunia
Patient may sit on one buttock
Pelvic Floor Disorders
Look for trigger points using cotton tipped applicator and gentle digital examination
Pelvic organ prolapse may be present
Iliopsoas Tenderness
May become obvious during the observation of gait and movement as well as the physical exam findings
GI
Irritable Bowel Syndrome (IBS)
Recurrent abdominal pain on average at least 1 day/week in the last 3 months, associated with two or more of the following criteria
Related to defecation
Associated with a change in the frequency of stool
Associated with a change in the form (appearance) of stool
Criteria should be fulfilled for the last 3 months with symptom onset ≥6 months prior to diagnosis
Symptoms alone may be used to diagnose IBS per Rome criteria (see ‘Learn More – Primary Sources’)
Depending on other GI symptoms, a few more tests may be ordered such as CRP if suspicion for inflammatory bowel disease
Abdominal bloating/rectal mucous are suggestive of but not diagnostic of IBS
Note: Deep infiltrating rectovaginal endometriosis may cause similar presentation
Chronic Appendicitis
Usually acute in presentation with peritoneal findings
In some patients, may have intermittent pain with normal CBC
Debate as to whether this is a true clinical rather than histological diagnosis
Hernia
Usually asymptomatic until incarceration occurs
Diverticulosis
Usually asymptomatic and noted on colonoscopy
May be associated with constipation and lower abdominal pain
Abdominal Migraine
May occur in adults
Unpredictable paroxysms of abdominal pain associated with
Nausea/Vomiting | Headache | Photophobia | Palor
No other explanation
Case reports, based on a diagnosis of exclusion
May be relieved with pregnancy
Female/Male ratio is 9:1 with average age of 31
May not always be associated with headache
Treatment: Patients respond well to NSAIDs, antiemetics and possibly sumatriptan
Other GI Disorders to Consider
Infectious causes
Signs/symptoms of GI infection, some of which may appear in the red flag section above
Vasculitis syndromes
Reason for abdominal pain in Systemic Lupus Erythematosus (SLE)
GU
Interstitial Cystitis
Can be either a primary cause, a component, or a secondary effect of chronic pelvic pain
Typical history of multiple suspected/treated UTIs, negative cultures
Psychosocial Issues
Psychological and social issues may occur in association with chronic pelvic and abdominal pain
It may be difficult to determine causality
Depression and sleep disorders may be a result rather than a cause
Nevertheless, proper management and treatment may improve quality of life
Referral to mental health professionals can be beneficial for both diagnosis and management depending on the clinical scenario
Part 3: Additional Diagnoses Following Typical Evaluation With Negative Results
Above patient received thorough history and physical
No findings on blood work and urinalysis
Review of previous imaging, endoscopy and laparoscopy notes did not reveal any pathology
What next?
Time to Consider Genetic Syndromes?
Some patients will reach a point where they have undergone multiple evaluations
Genetic disorders associated with abdominal pain may not have been considered
While these disorders are rare or unusual, the typical presentation may fit the present scenario of a thorough work-up by multiple specialists, but no clear diagnosis
Female (especially for the autosomal dominant disorders below)
Multiple treatments including surgeries without improvement
Ongoing pain but no diagnosis, sometimes for several years
Below are a few genetic syndromes that could be placed on the differential
Acute Intermittent Porphyria (AIP)
Autosomal dominant inheritance (low penetrance so may not a have an obvious family history)
More commonly seen in women
Drugs (e.g. barbiturates, sulfonamides), alcohol, infection, stress, starvation, and hormonal changes can precipitate attacks
Can be managed by specialists
Most individuals without the mutation will be asymptomatic
There is an association with hepatocellular carcinoma
The HBMS gene, which codes for the enzyme hydroxymethylbilane synthase (also known as PBG-D) is only 50% functional
PBG-D is in the heme synthesis pathway and therefore a defect in the enzyme can lead to build up and release of precursors from the liver
5-aminolevulinic acid (ALA): A neurotoxin and appears to cause clinical findings and complications
Porphobilinogen (PBG): Primary precursor measured in urine for diagnostic testing
Presentation
Suspect AIP in the following
Abdominal pain which may be severe (usually lasting 2 weeks)
No peritoneal signs
Patients may complain of pain in thighs
Commonly associated with
Nausea & Vomiting | Hypertension | Tachycardia
Other less common findings
Neurologic
Mental status changes (up to 30%): Depression | Psychosis | Anxiety |
CNS: Seizures | Peripheral neuropathies |Weakness
Lung function
Respiratory paralysis
Genitourinary – bladder
Retention
Dysuria
Incontinence
Sometimes urine will be red/brown urine
Laboratory changes such as hyponatremia
Diagnosis
Increased urinary concentration of PGB (primary test) and ALA
Most likely to be positive during or following a painful attack
Consider urine test or referral to genetics center for work-up and testing
Molecular testing is also available to detect the pathogenic variant (important for family studies)
Other types of porphyria: Hereditary coproporphyria (HCP) and variegate porphyria (VP)
Both present with the similar abdominal pain, but patients may also exhibit skin lesions when exposed to sunlight
Familial Mediterranean Fever
Autosomal recessive inheritance pattern
This disorder can be found on many of the expanded prenatal genetic carrier screening panels
Relatively common in populations from the Mediterranean region
Armenian, Arab, Turkish, or Jewish ancestry
Usually manifests in childhood or teenage years, but may appear much later in life
Can be managed by specialists and while individuals may be asymptomatic between attacks, there is an association with amyloidosis leading to renal disease
MEFV reduces the activity of the pyrin protein, that is important in the regulation of inflammatory processes
Both copies of the MEFV gene will have pathogenic mutations
A prolonged, inappropriate inflammatory response leads to abdominal pain, serositis and related findings
Presentation
Recurrent episodes of pain
Abdomen
Chest
Joints
Note: Pain episodes can last hours to days, and vary in frequency
Other target areas
CVS
Pericarditis
GU
Nephrotic syndrome
Renal amyloidosis
Renal failure
Lab values
WBC >30,000/mL
Elevated ESR
In addition, the following may be present
Fever (common)
Rash (erysipelas-like erythema)
Headache
‘Prodrome’: Uncomfortable, mild abdominal discomfort or sensations in other target areas
Diagnosis
There are scoring systems based on clinical major and minor findings
Molecular testing confirms pathogenic mutations in both copies of the MEFV gene
Hereditary Angioedema
Autosomal dominant inheritance
Disorder that is associated with severe swelling (angioedema) of multiple systems
GI swelling results in abdominal pain
May be associated with other autoimmune disorders
Mostly seen in women
Associated with triggers (e.g. trauma, anxiety, stress) but often no obvious factor is identified
Usually presents in childhood with worsening following puberty but may occur later in life
Can be managed by specialists, which is important considering due risk for laryngeal swelling and airway obstruction
New drugs are being studied to prevent and manage this disorder
Mutations in the SERPING1 gene cause type I and type II
SERPING1 regulates C1 inhibitor protein which controls inflammation
Pathogenic variants cause C1-inhibitor deficiency and corresponding inappropriate inflammatory responses
Excessive bradykinin protein fragments cause fluid leakage through blood vessel walls
Mutations in the F12 gene cause some cases of type III
F12 regulates coagulation factor XII that plays a role in clotting and the bradykinin protein
Pathogenic variants in F12 cause increased activity in factor XII and increased bradykinin
Presentation
Recurrent episodes of severe swelling (angioedema) with the following target areas
GI
Abdominal pain
Vomiting
Diarrhea
Intestinal edema
Limbs
Face
Airway
Laryngeal/Pharyngeal swelling
Skin
Rash: Erythema marginatum (non-itchy)
Neurologic
Peripheral neuropathy
Impaired sensation
Prodrome (occurs 50% of the time)
Local discomfort | Erythema marginatum | Fatigue | Muscle aches
Note: Pain episodes can last for days but frequency and duration are variable
Diagnosis
C4 levels: Mostly decreased
C1-Inh activity: reduced
Molecular testing to confirm pathogenic variant in a copy of the specific gene
The Wrap Up
Despite best efforts, some patients are left without a clear diagnosis but with ongoing pain
Goal of treatment may be to ameliorate and better understand symptoms rather than make the patient completely pain free
Important for the patient and clinician to be aligned regarding aim of diagnosis and treatment plan
It is not always easy to distinguish between pelvic vs abdominal pain, especially in the lower quadrants
Genetic causes, while rare, warrant consideration
Diagnosis often takes years or decades
Presentation often involves multiple prior surgeries
AIP and hereditary angioedema generally affect women
Ask patients about some of the associated symptoms, such as swelling for angioedema or weakness and/or neuropathies for AIP
Refer to genetic specialists if unsure of the diagnosis
All clinical features are generally not present, and diagnosis may not be clear cut
A detailed family history and genetic targeted history and physical may elucidate an underlying genetic disorder
Screening tests can be ordered by non-genetic professionals, but if unsure, a genetic consultation can provide an avenue for appropriate testing
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