Table of Contents

• Learning Objectives
• The Case
• Evaluation of Pelvic/Abdominal Pain
• Differential Diagnosis for Abdominal ABD/Pelvic Pain
  • Gynecology
  • Other Potential Pathologies
• The Wrap Up: Negative Work-up and Persistent Pain
  • Consider Acute Hepatic Porphyria (AHP)
  • What Should Tip You Off That This May Be AHP?
  • AHP Testing and Diagnosis Pearls
  • Treatment of AHP
  • Pregnancy and AHP
• Learn More – Primary Sources
• Independent Organizations Focused On Porphyria

Learning Objectives

• Discuss the causes of acute intermittent abdominal/pelvic pain
• Describe a typical work up for acute intermittent abdominal/pelvic pain in women
• Recognize diagnostic clues that suggest including acute hepatic porphyria (AHP) in the differential diagnosis  

THE CASE

History of Present Illness

• 32-year old female G0P0
  • Day 21 of her menstrual cycle of a regular 32-day cycle
  • Recently moved and seeing you for her first gyn visit
• Presenting with an acute exacerbation of intermittent abdominal/pelvic pain
  • Rates the pain at 8/10
  • She was out drinking with friends the day before and hadn’t had much to eat
• History of recent acute pain  
  • Was seen in the ED 3 days previously with signs and symptoms of cystitis (including hematuria), including dysuria and lower abdominal and pelvic pain
  • Treated with sulfamethoxazole-trimethoprim

Additional History

• Pain has always occurred in lead up to and around her menses
  • No positions or activities make pain better or worse
  • Sometimes pain radiates to her back
  • No change in bowel habits
• Has experienced pain episodes intermittently over several years since late teens
  • Associated with nausea/vomiting when pain most intense
  • Periodic reddish urine upon collection attributed to UTI
  • Generally treated with expectant management and NSAIDs as needed, with little relief
• Past medical history: Occasional anxiety but attributes this to stress at work and concern related to her chronic pain and ongoing uncertainty of the cause of her symptoms
• Previous surgical history: Diagnostic laparoscopy 1 year ago – negative
• Family history: Paternal aunt had hysterectomy (unsure of indication) and history of mental health issues (unsure of diagnosis)
• Medications
  • Ibuprofen 600mg TID when needed
  • Progesterone only pills daily without improvement in symptoms
  • No known drug allergies

Physical

• Abdominal exam
  • Diffusely tender to palpation | Normal bowel sounds | Peritoneal signs not present
• Pelvic exam
  • No evidence of infection or CMT | General tenderness

Previous Labs

• Negative hCG
• Urine toxicology negative
• WBC normal
• Mild hyponatremia

Radiology

• Normal pelvic ultrasound with bilateral flow to ovaries

EVALUATION OF PELVIC/ABDOMINAL PAIN

History

• Description of pain and timing
  • Periodic vs constant | Quality of the pain: crampy, sharp, dull, deep
  • What improves / worsens pain
  • Temporal associations: intercourse, orgasm, menses, meals, bowel movements
• Previous treatments
  • Medications | Hormones | Surgery
• Social history
  • Abuse or trauma history
  • Drug use / abuse
  • Consider depression screen with PHQ-2, PHQ-9 if the 2 values screen is positive
• Other signs / symptoms
  • Loss of appetite
  • Rectal bleeding
  • Abnormal uterine bleeding
• Family History
  • Breast, ovarian, colon cancers
  • Other family members with similar pain syndromes

Physical Exam

• General
  • Gait, affect, positioning
• Musculoskeletal
  • Paraspinous muscles
  • Abdominal muscles (pain when palpating in presence of flexed abdominal muscles is indicative of myofascial etiology [Carnett’s sign])
  • Psoas sign
  • Pelvic joints
• Abd: Bowel sounds | Palpation in standing and reclining for pain, hernia or mass
• GU: Suprapubic exam | Vulvar exam | Speculum and bimanual pelvic exam (typically start with no hand on the abdomen hand to assess for uterine / adnexal tenderness) | Pelvic floor exam for tension | Trigger points

Further Diagnostic Workup

• Labs
  • CBC | Metabolic panel | Urinalysis | STI screen
• Imaging
  • Pelvic ultrasound with transvaginal component is sensitive for GYN etiology
  • Abd/Pelvic CT with contrast may better describe bowel and intraperitoneal etiologies
• Surgical evaluation: Laparoscopy
  • Histology of lesions removed at surgery remains a method for definitive diagnosis of endometriosis (even with negative ultrasound report)
  • May detect ovarian or fallopian tube torsion, with treatment potentially possible during the procedure

DIFFERENTIAL DIAGNOSIS FOR ABDOMINAL ABD/PELVIC PAIN

Gynecology 

• Endometriosis
  • Typically presents with pain around menses, can progress to chronic, constant pain; confirmation via laparoscopy and/or biopsy
• Adenomyosis
  • Typically presents with menses-related pain, severe cramping with menses | While adenomyosis is defined histologically as “the presence of ectopic endometrial tissue (endometrial stroma and glands) within the myometrium” new imaging techniques such as ultrasound or MRI can aid in detection

Note: Both endometriosis and adenomyosis may be detected on ultrasound, but can also exist in the setting of a negative scan | Both may respond to combined OCP, progesterone-only hormonal treatments, or GnRH agonists | Surgical evaluation for endometriosis may be undertaken for diagnosis and treatment

• Adhesive disease
  • Usually in setting of past pelvic inflammatory disease (PID) or endometriosis
• Ovarian or Fallopian tube torsion
  • Absence of flow to adnexal structures is indicative
  • Note: periodic torsion can present as cyclic pain and show normal flow on ultrasound
  • Surgical evaluation may be necessary if these diagnoses are suspected
• Levator Ani / Pelvic Floor pain
  • On examination, pelvic floor muscles are often tight and tender: associated with dyspareunia
  • Assessed on exam with careful palpation | Myofascial trigger points usually present
  • Often treated with pelvic floor PT

Other Potential Pathologies

GI

• Irritable Bowel syndrome | Inflammatory bowel disease | Chronic constipation | Chronic appendicitis | Abdominal Migraine | Diverticulitis
• Consider GI referral for extended work-up if pain is associated with significant signs and/or symptoms (e.g, blood in stool)

Urinary

• Kidney stones | Infection | Interstitial cystitis (IC)
• General GU (genitourinary) work-up may include
  • Urinalysis looking for blood, WBC and infection | An ultrasound or non-contrast CT may help find kidney stones | A post void residual volume can be used to exclude retention due to outlet obstruction or neurologic issues | Cystoscopy may be done to look for other etiologies of bladder pain, especially if there is hematuria on microscopy | Cystoscopy may not be needed to make the diagnosis of IC

THE WRAP UP: NEGATIVE WORK-UP AND PERSISTENT PAIN

Consider Acute Hepatic Porphyria (AHP)

• Clinical presentation following a negative work-up is consistent with Acute Hepatic Porphyria (AHP) and therefore further diagnostic evaluation may include a random (spot) urine for porphobilinogen (PBG), δ‐aminolevulinic acid (ALA) and porphyrins
• There are four types of AHP: acute intermittent porphyria (AIP) is the most common; variegate porphyria (VP), hereditary coproporphyria (HCP) and ALAD-deficient porphyria (ADP) are the other types
• Timely diagnosis is critical because AHP may mimic other diseases/conditions and lead to negative outcomes, including potentially unnecessary treatments, surgeries and hospitalizations
  • 65% of AHP patients with recurrent attacks reported chronic symptoms between attacks
  • Risk for potential long-term complications: Elevated risk for primary liver cancer (hepatocellular carcinoma) | Chronic renal disease and hypertension | Lasting neurologic and mental health issues
  • Progestins, among other drugs often used in women’s health, could exacerbate symptoms and incite acute attacks of abdominal pain
  • Management and treatment options are available

What Should Tip You Off That This May Be AHP?

While AHP can be difficult to diagnose due to the non-specific symptoms and overlap with other more common conditions, clues are present in this case. For educational purposes, the patient in this case had numerous triggers and clues leading to porphyria, but not all may be present in all cases.

• Intermittent cyclical severe pain leading to multiple visits associated with psychological symptoms such as anxiety
• Worsening or triggering of symptoms occurring with certain medications, such as sulfonamides
• Red/brown urine can be observed if urine is exposed to light, especially during a painful attack (can be mistaken for or masked by hematuria)
• Usually begins in women at the onset of puberty, typically effects women in their second to fourth decades of life
  • More predominant in women as hormones associated with the menstrual cycle can precipitate an attack
  • Attacks can be unpredictable, but cyclical attacks in women often begin during the luteal phase of the menstrual cycle when progesterone levels are elevated
  • Progesterone-containing medications have also been associated with attacks
• Often symptoms of AHP are nonspecific and therefore delays in diagnosis and numerous misdiagnoses are common

General Features That May Point to Porphyria

• Note: AHP can present in variable ways | Patients may not have all of these symptoms
• Abdominal pain that is severe, unremitting and diffuse
  • Usually the hallmark sign of an attack
  • Pain may be described as cramping; may also present with pain in the chest, neck, thighs, arms and back
• Weakness: proximal muscle weakness, fatigue
• Psychological (CNS) symptoms
  • Confusion, anxiety, insomnia, hallucinations, seizure
• Autonomic manifestations: nausea, vomiting, constipation, hypertension, tachycardia, hyponatremia
• Less common types of AHP (VP & HCP) may present with blistering lesions on sun-exposed skin

AHP Testing and Diagnosis Pearls

• Consider including AHP on the differential for a patient with unexplained, recurrent abdominal pain episodes lasting >24 hours, especially with additional psychological and/or neurological symptoms
• One typical method: random (spot) urine for PBG, ALA and porphyrins, normalize results to urine creatinine
  • Why are urine biomarkers elevated?
    • Acute hepatic porphyria is a group of metabolic disorders that result from a deficiency in one of the enzymes in heme biosynthesis in the liver
    • Induction of this pathway leads to the accumulation of heme pathway intermediates (PBG and ALA) that are neurotoxic and associated with attacks and other symptoms
• Genetic Testing
  • Can help confirm specific type of AHP, rule out AHP, or identify at-risk family members

Note: The optimal time to test is during or shortly after an attack when ALA and PBG levels have spiked | ALA and PBG levels may fall when symptoms resolve

Management and Treatment of AHP

Physicians may consider consulting with an expert in porphyria (e.g. hematologists, hepatologists, or geneticists)

• Avoidance of attack triggers that can induce the heme biosynthesis pathway in the liver
  • Hormonal fluctuations due to hormonal medications (e.g. progestins, OCPs), menstrual cycle, pregnancy and postpartum
  • Certain Drugs (commonly those that induce cytochrome P450) (see APF Drug Database below)
  • Binge drinking alcohol
  • Fasting/Low caloric diet: particularly if on a restrictive, low-carb diet
  • Infections, stress, surgery
• Treatment/prevention of acute attacks
  • Hemin is approved for the amelioration of recurrent AIP attacks. Some doctors prescribe it for attack prophylaxis
  • RNA interference therapy is approved for the treatment of AHP in adults
  • GnRH agonists may be used for women experiencing acute attacks related to their menstrual cycles
  • Glucose and carbohydrate loading may downregulate the heme biosynthesis pathway
• Management of acute attack pain and other chronic symptoms
  • Pain medication (opioid and non-opioid)
  • Medications for symptomatic management | nausea, hypertensive crises, neuropathy, seizures, metabolic changes, anxiety, depression
  • Liver transplantation is rare and limited to severely affected patients

Pregnancy and AHP

• Hormonal changes may worsen AHP in some individuals
  • Some fertility treatments have also been associated with triggering acute attacks
• Prenatal counseling
  • Autosomal Dominant Inheritance Pattern with low penetrance: 50% chance with each pregnancy of passing mutation on to offspring

Commercial Support

The educational materials, including the hypothetical case study, are sponsored by Alnylam Pharmaceuticals. They are not intended to replace a healthcare professional’s independent clinical judgment. The “Learn More Primary Sources” below are provided for reference. Alnylam Pharmaceuticals does not endorse the “Learn More” sites below and is not responsible for their content.

Learn More – Primary Sources:

ACOG Practice Bulletin 218: Chronic Pelvic Pain

Adenomyosis: A Clinical Review of a Challenging Gynecologic Condition (Struble et al. J Minim Invasive Gynecol, 2016)

Diagnosing adenomyosis: an integrated clinical and imaging approach (Chapron et al. Hum Reprod Update, 2020)

ACR Appropriateness Criteria: Acute Nonlocalized Abdominal Pain

Relevance of the Endoscopic Evaluation in the Diagnosis of Bladder Pain Syndrome/Interstitial Cystitis (Morlacco et al. Urology, 2020)

Evidence-Based Medicine Approach to Abdominal Pain (Natesan et al. Emerg Med Clin North Am, 2016)

ACOG Practice Bulletin No. 114: Management of Endometriosis 

ASRM: Treatment of Pelvic Pain Associated with Endometriosis: A Committee Opinion

Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome: AUA Guideline Amendment (Hanno et al. J. Urol, 2015)

Common Questions About the Evaluation of Acute Pelvic Pain (Bhavsar et al. Am Fam Physician, 2016)

Myofascial Pelvic Pain and Related Disorders (Bonder et al. Phys Med Rehabil Clin N Am, 2017)

Pelvic floor physical therapy in the treatment of pelvic floor dysfunction in women (Wallace et al. Current Opinion in Obstetrics and Gynecology, 2019)

Acute Pelvic Pain (Dewey and Wittrock. Emerg Med Clin North Am, 2019)

Imaging of Acute Pelvic Pain: Nonpregnant (Olpin and Strachowski. Radiol Clin North Am, 2020)

Rare Diseases Clinical Research Network: The Acute Porphyrias

NORD: Acute Intermittent Porphyria

Pathogenesis and Clinical Features of the Acute Hepatic Porphyrias (Bonkovsky et al. Mol Genet Metab, 2019)

Acute Hepatic Porphyrias: Review and Recent Progress (Wang et al. Hepatol Commun, 2018)

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks (Gouya et al. Hepatology, 2020)

Independent Organizations Focused On Porphyria

American Porphyria Foundation

US Porphyrias consortium

European Porphyria Network (EPNET)

American Porphyria Foundation: Drug Database