Mechanism of Bone Metastases

Mechanism of Bone Metastases
by: Dr.Priya Gopalan

Outline
* Background
* Predictors of metastasis to bone
* Tumor cell homing to bone
* Tumor cell interaction with bone
* Therapeutic interventions

Bone Metastases
Types of bone metastases
Diagnosis
* Bone scan - best for osteoblastic lesions
* MRI
* CT scan with bone windows
* PET-CT
* Plain films
* Markers of bone turnover

Prognosis
Relative risk ratios during zoledronic acid therapy
(skeletal-related events)
NSCLC and solid tumors
High vs. low NTX levels
Reasons for preferential metastasis to bone
* Highly vascular organ (sluggish blood flow)
* Paget’s “seed-and-soil” hypothesis
o Bone marrow niche provides:
+ Chemotactic signal to home (e.g. SDF-1)
+ Adhesion receptors to extravasate
+ Growth factors to proliferate (e.g. TGF-b, IGF-1)
Predictors of metastasis to bone (Breast Cancer)
Tumor cell homing
* Organs that are primary sites of breast cancer metastasis produce high levels of SDF-1
* Blocking CXCR4 in vitro inhibited prostate cancer migration through bone marrow endothelial cells
* Blocking CXCR4 in vivo reduces bone metastases in breast and prostate cancers
* CXCR4/ SDF-1 axis also important in
o NSCLC:
o RCC:
* Integrins may also direct organ-specific mets
o When avb3 is overexpressed on breast cancer cells, bone metastases are enhanced
o CXCR4 binding to SDF-1 activates avb3 and mediates its binding to endothelial cells
o avb3 antagonist inhibits bone colonization by avb3-expressing tumor cells
o a2b1 on prostate cancer cells supports bone colonization
* Other chemokines produced by OBs
o Osteopontin
o Bone sialoprotein

Normal bone remodeling
Osteoprotegerin
Osteoblasts/osteoclasts interaction with tumor cells
Osteomimicry by tumor cells
Therapeutic targets
* Osteoblastic lesions
o Endothelin-1 (anti-receptor antibody)
* Osteolytic lesions
o Bisphosphonates
o RANKL (anti-RANKL antibody)
o PTHrP
o Osteoprotegerin (Fc-OPG)
* Endothelin A receptor inhibitor, Atrasentan
o M00-211 trial - Double-blinded, randomized, multi-institutional placebo-controlled Phase III trial with 809 patients with hormone-resistant metastatic prostate cancer

+ Endpoint - TTP
+ Results
# TTP HR 0.89 (CI 0.76,1.04, p=0.136)
# Median time to bone alk phos progression 505 vs 254 days (p<0.01)

Bisphosphonates
* Long-term treatment of osteolytic metastases
* Preferentially bind areas of high bone turnover
* Aminobisphosphonates
o e.g. zoledronate, aledronate, risedronate
o Block prenylation of osteoclast proteins (small GTP-binding proteins, e.g. ras and rho), leading to apoptosis
* Non-aminobisphosphonates
o e.g. clodronate, etidronate
o Inhibit ATP-dependent enzymes, leading to apoptosis
* Also may inhibit tumor adherence to bone, inhibit angiogenesis, reduce IL-6 production

Bisphosphonates-clodronate
* Clodronate approved in Europe but not US
* Double-blind, placebo-controlled, multicenter trial with 1,069 patients with operable breast cancer randomized to clodronate or placebo
o 1° endpoint - relapse in bone
o 2° endpoints - relapse in other sites, mortality, toxicity
o Significant reduction in bone metastases during medication period (HR 0.44, CI 0.22-0.86, p=0.016), but not in total follow-up period
o Reduced mortality (98 in clodronate arm, 129 in placebo arm, p=0.047)

Bisphosphonates-pamidronate
* 754 pts with metastatic breast cancer (with osteolytic bone metastases) randomized to pamidronate or placebo
o 1° objective - skeletal events per year and time to 1st skeletal-related event (SRE)
o Only 115 of 367 (31.3%) on pamindronate arm and 100 of 384 (26.0%) on placebo arm completed the study
o Pamidronate arm - 2.4 skeletal events/yr; placebo arm - 3.7 events/yr (p<0.001); also observed longer time to 1st SRE in pamidronate arm (12.7 vs 7 months, p<0.001)
o Limited by significant number of pts who did not complete study
Bisphosphonate - zoledronate

* 1803 premenopausal women with Stage I and II breast cancer randomized to tamoxifen/anastrozole ± zoledronic acid
* 1° endpoint DFS; 2° RFS, OS; explor: bone met-free survival
* DFS (HR 0.643 [CI 0.46-0.91], p=0.011)
* RFS (HR 0.653 [CI 0.46-0.92], p=0.014)
* No change in OS
* See effects outside bone

Bisphosphonates - zoledronate (prostate cancer)
* Zometa 039 trial: 643 men with hormone-refractory metastatic prostate cancer received zoledronate 4 mg, 8mg then 4mg, or placebo for 18 months
o Zometa decreased SREs and pain, but no difference in disease progression or performance status
* Trials with pamidronate and clodronate in metastatic prostate cancer showed no significant benefits
* Randomized, placebo-controlled Phase III trial, with 773 pts with lung, RCC, etc. metastatic to bone randomized to zoledronate vs placebo q3 months for 21 months
* 1° endpoint - % patients with ≥1 SRE
* Zolendronate delayed the onset and reduced risk of skeletal-related events compared to placebo in pts with bone metastases due to lung cancer or other solid tumors.
o Reduced time to 1st SRE with treatment (236 vx 155 days, p=0.009), decreased number of events/year (1.74 vs. 2.71, p=0.012), HR developing skeletal event reduced in zoledronate arm (HR 0.693, p=0.003)

Bisphosphonates
* Osteonecrosis of the jaw

Other therapies

Mechanism of Bone Metastases.ppt

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Cutaneous Toxicities of Cancer Therapy

Cutaneous Toxicities of Cancer Therapy
By:Dr.Saiama Waqar

Outline
* Alopecia
* Hyperpigmentation
* Hand-foot syndrome
* Radiation sensitivity and recall
* Hypersensitivity
* Nail dystrophies
* Extravasation injuries
* Skin toxicity from targeted therapies
* Conclusion

Alopecia
* Drugs that target rapidly dividing cells often affect the proliferating cells in the hair follicle
* Terminal hair follicles with rapid matrix formation more affected (scalp more than body hair, eyebrows, eyelashes)
o completely lost in a short time: transplant
o gradually lost over several weeks: cyclic chemotherapy
* Methotrexate: affects the follicle melanocytes, resulting in depigmented band of hair, “flag sign”
* Visible regrowth within 3-6 months
* Often regrows with a change in color or texture (switching from straight to curly), mechanism of change unclear
* Psychologically, one of the most stressful side effects

Grading of alopecia
Grade
Minimal loss, grade 1
< 25%; obvious to the patient but not necessarily to others

Moderate loss, grade 2
25 to 50 %; obvious thinning of scalp hair but not enough to lead to the use of a wig or alternate head covering

Severe loss, grade 3

> 50% of hair lost; generally indicates the need for a wig or alternate head covering in those for whom alopecia is a major concern

Chemotherapy drugs causing alopecia

* Often
o Bleomycin
o Etoposide
o Methotrexate
o Mitoxantrone
o Paclitaxel
* Common
o Cyclophosphamide
o Daunorubicin
o Doxorubicin
o Docetaxel
o Idarubicin
o Ifosphamide
o Paclitaxel
* Infrequent
o 5-FU
o Hydroxyurea
o Thiotepa
o Vinblastine
o Vincristine
o Vinorelbine
* Rare
o procarbazine

Prevention of alopecia
* scalp tourniquets:
o pneumatic device placed around the hairline during chemo infusion
o inflated to a pressure >SBP
o Several studies: effective for preventing hair loss
+ utilized different techniques, variation in chemotherapy regimens, tourniquet pressure, sample size, and criteria to assess alopecia (data difficult to interpret)
o Side effects: headache, varying degrees of nerve compression

Prevention of alopecia
* Hypothermia with scalp icing devices:
o Vasoconstriction of scalp blood vessels, less absorption of chemo as hair follicles less metabolically active at 24C
o ice turban, gel packs, cool caps, thermocirculator, room air conditioner
o 50-80% response, though variable chemotherapy regimens and definitions of alopecia, small sample size
* Not effective in liver disease
o Delayed drug metabolism, persistent levels beyond protective period
* Scalp metastases:
o mycosis fungoides, limited to scalp. CR after chemo without scalp cooling
o 61 pts with met breast cancer and liver dysfunction, 1 pt scalp met

Preventive devices
* 1990- FDA stopped sale of these devices citing absence of safety or efficacy data
* Cranial prostheses (wigs) and scarves use encouraged

Pharmacologic interventions for alopecia
* Topical minoxidil (shorten time to maximum regrowth, did not prevent alopecia)
* AS101(NSCLC pts: garlic-like halitosis and post-infusion fevers)
* Alpha tocopherol (cardioprotection for doxorubicin, noted less alopecia)
* Topical calcitriol (cell lines- protects cancer cells)
* IL-1(rats, cytarabine, cell cycle specific, protected)
* Inhibitors of p53 (mice deficient p53, no alopecia)

Hyperpigmentation
* usually resolves with drug discontinuation
o gingival margin pigmentation seen with cyclophosphamide is usually permanent
* Patterns of pigmentation:
o Diffuse
o Local at site of infusion
* Sites of pressure /trauma
o Hydrea and cisplatin
* Busulfan
o “busulfan tan” can mimic Addison's disease.
o Although busulfan can also cause adrenal insufficiency, the skin change is 2/2 toxic effect on melanocytes
o Distinguish busulfan toxicity from true Addison's disease by normal levels of MSH & ACTH
* Liposomal doxorubicin
o macular hyperpigmentation over the trunk and extremities, including the palms and soles
o not been described with unencapsulated doxorubicin

Drugs causing hyperpigmentation

HAND-FOOT SYNDROME
* also known as palmar–plantar erythrodysesthesia (PPE)
* originally described in patients receiving high-dose cytarabine
* skin lesions begin as erythema and edema of the palms or soles and is associated with sensitivity to touch or paresthesia
* can progress to desquamation of the affected areas and significant pain

Hand foot syndrome
Acral erythema from docetaxel

Pathogenesis
* Unclear: small capillaries in the palms and soles rupture with increased pressure from walking or use, creating an inflammatory reaction
* formulation of drugs and duration of exposure can impact the incidence
o liposome-encapsulated doxorubicin more than standard formulation
o 5-FU bolus lower than CIVI and capecitabine (converted into 5-FU in vivo)

Hand foot syndrome Grading
Grade
Signs and symptoms

1 Minimal skin changes or dermatitis (eg, erythema) without pain
2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function
3 Skin changes with pain, interfering with function

Treatment
* No proven preventive therapy
o Pyridoxine (vitamin B6) may help reduce the incidence and severity
o Celecoxib reported to reduce incidence
* Management largely symptomatic with reduction of drug doses where appropriate
* emollients and protective gloves can be helpful

Radiation sensitization and recall
* Some chemotherapeutic agents can sensitize the skin to radiation
* recall phenomenon in previously irradiated tissue (wks to yrs after RT)
o when chemotherapy is administered
* Exact mechanism not clearly understood,
o radiation effects on the microvasculature
o altered cutaneous immunologic responses
* maculopapular eruptions with erythema, vesicles, desquamation
o mild rash to severe skin necrosis

Radiation sensitization and recall
* No specific therapy recommended
o topical corticosteroids
o Ultraviolet radiation
* caution about sun exposure
o wear protective clothing
o sunscreen products
+ 5-FU increases photosensitivity to sunlight
+ MTX may reactivate a sunburnes of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6

Hypersensitivity reactions
* Can occur either from drug itself or from solubility vehicle (eg. Cremophor for paclitaxel)
* Prevention: premedicate
o Steroids (dexamethasone), H1 blockers (benadryl), H2 blockers (pepcid)
* Management of hypersensitivity reactions:
o epinephrine, hydrocortisone, and histamine blockers, along with monitoring of BP

Drugs causing hypersensitivity
NAIL DYSTROPHY
* Color changes
o Mee’s lines - transverse white
o hyperpigmentation
* Beau’s lines - transverse grooves/lines
o related to the effect of chemotherapy causing decreased nail growth
* Paronychia -inflammation of the nail fold
o Seen with cetuximab

Beau’s lines
* Onycholysis (separation of the nail plate from the nail bed)
o can be painful
o anthracyclines, taxanes (especially weekly paclitaxel), and topical 5-fluorouracil
* frozen-glove study to prevent docetaxel-induced onycholysis & cutaneous toxicity
o 45 patients, frozen glove for 90 minutes on the right hand, using the left hand as control
o Frozen glove reduced the nail and skin toxicity

Grading of nail changes
Grade
Nail changes/toxicity

1 Discoloration, ridging (koilonychias), pitting
2 Partial or complete loss of nail(s), pain in nailbed(s)
3 Interfering with ADL
Nail changes with docetaxel

Drugs causing nail changes
* Pigmentary changes
o Bleomycin
o Busulfan
o Cisplatin
o Cyclophosphamide
o Docetaxel
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyurea
o Idarubicin
o Ifosfamide
o Melphalan
o Methotrexate
o Mitomycin
o Mitoxantrone

* Onycholysis
o Paclitaxel
o Docetaxel
o Gemcitabine
o Capecitabine
o Cyclophosphamide
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyruea
* Inflammatory changes
o Gefitinib
o Cetuximab
o Capecitabine
o Docetaxel
o Paclitaxel

Extravasation injury
* The accidental extravasation of intravenous drugs occurs in approximately 0.1% to 6% of patients receiving chemotherapy
* Depending on the agent and amount, the sequelae of extravasation can range from erythema and pain to necrosis and sloughing of the skin
* The most toxic drugs are the vesicants, such as the anthracyclines, vinca alkaloids, nitrogen mustards, as well as paclitaxel and cisplatin

Vesicants and irritants
Treatment of extravasation
* immediate discontinuation of the infusion
* cooling with ice packs
o warm soaks for vinca alkaloids
* for persistent/progressive local symptoms - surgical consult
* early local debridement of can reduce extent of later injury

Extravasation of vinblastine in a 57-year-old male receiving chemotherapy for bladder cancer

Antidotes for extravasation
o topical DMSO (dimethyl sulfoxide) to enhance absorption of the extravasated drug, routine use still controversial
o Thiosulfate -nitrogen mustard extravasation (injection of a 1/6 molar solution into the area of extravasation)
o Dexrazoxane - anthracycline extravasation
* Regardless of antidote, local therapy, and prompt surgical intervention is paramount

Skin Toxicity from targeted therapy
* Because the EGFR is also expressed by basal keratinocytes, sebocytes, the outer root sheath, and some endothelial cells, agents that inhibit EGFR are associated with dermatologic side effects
Erlotinib eruption on the arms

Cutaneous reactions associated with molecularly targeted agents
Monoclonal antibodies to EGFR
Infusion reactions; acneiform eruption; paronychial inflammation; photosensitivity
* Cetuximab, panitumumab

EGFR pathway inhibitors
Acneiform eruption; paronychial inflammation; photosensitivity
* Erlotinib
* Gefitinib
* Lapatinib

Multitargeted tyrosine kinase inhibitors
Skin exanthem; SJS; acute generalized exanthematous pustulosis; Sweets syndrome; hand-foot syndrome; photosensitivity; pigmentary changes, hair depigmentation; alopecia

* Imatinib
* Dasatinib
* Sorafenib
* Sunitinib

EGFR-inhibitor induced skin changes
* (a-c) stratum corneum thickness, (d) apoptosis (apoptotic cells by 10,000).
* On-therapy (gefitinib) biopsy specimen showing (e) keratin plugs and micro-organisms in dilated infundibula and (f) acute folliculitis.

Cetuximab skin toxicity
Moderate rosacea-like eruption from cetuximab
80 year old patient receiving cetuximab and radiation for nasopharyngeal cancer

Erlotinib rash treatment
Severity of Rash
Treatment Protocol
Mild
Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily.
Moderate
Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required, until resolution of the rash by one severity grade. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water.
Severe
Stop erlotinib therapy for 1 week and restart at 100mg once-daily. Treatment of rash with topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water until resolution.
Dose modification guidelines for cetuximab (Erbitux) based upon dermatologic toxicity

Cutaneous Toxicities of Cancer Therapy.ppt

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Acute Intermittent Porphyria

Acute Intermittent Porphyria
Heme/Onc Grand Rounds
By:Jane Chawla, M.D.

History of Present Illness
Physical Exam & Laboratory Data

* VS: T 36.2 P 142 R 20 BP 178/112
* Gen: Sleepy but arousable, AxO x3
* HEENT: PERRL, EOMI, OP Clear
* Neck: Supple, no LAD
* CV: tachy, regular rhythm, no m/g/r
* Lungs: CTAB
* GI: soft, ND, mild periumbilical discomfort to palpation
* Extr: no c/c/e
* Skin: No rashes or skin lesion
* Neuro: CN II-XII intact, strength 4/5 throughout, paresthesia in bilat lower extremities, 2+ reflexes, upgoing toes



Labs:
Random Problem List?
* Hyponatremia
* Tachycardia
* Hypertension
* Elevated Creatinine
* Abdominal Pain
* Transaminitis
* Weakness
* Cortisol – wnl
Cosyntropin Stim Test – wnl
Urine lytes → SIADH
* EKG – sinus tachycardia
CT Angio (-)
Urine VMA/metanephrine (-)
* Renal Ultrasound – wnl
responded to fluids
* LFTs – Mild transaminitis
CT Abdomen/Pelvis (-)
Hepatitis panel (-)

PORPHYRIA
Heme central to understanding Porphria
* Heme is part of hemoglobin, myoglobin, catalases, peroxidases, and cytochromes
* Heme is made in every human cell (85% in erythroid cells & much of the rest in the liver)
* First enzyme in heme synthesis pathway is ALA synthetase (ALAS)
* Increase demand induces ALAS
* Heme downregulates ALAS by feedback inhibition
* Partial block in this pathway induces ALAS and causes accumulation of heme precursors upstream from block

Porphyria is a disruption in the heme pathway
* Group of metabolic diseases resulting from a partial deficiency of an enzyme in the heme biosynthetic pathway
* Seven enzymes in the pathway
* Four of the porphyrias cause acute attacks
* Increased demand for heme can precipitate attacks secondary to overproduction of toxic heme precursors (porphyrins, ALA)
* The porphyrins have no useful function and act as highly reactive oxidants damaging tissues

Overview of the Seven Porphyrias
Overview of the Four Acute Porphyrias
* Four acute porphyrias cause acute, self-limiting attacks that lead to chronic and progressive deficits
* Symptoms of acute attacks mimic other diseases and increase the potential for misdiagnosis.
* Acute porphyrias are clinically indistinguishable during acute attacks, except the neurocutaneous porphyrias (variegate porphyria and hereditary coproporphyria) can cause dermatologic changes
* Acute attacks lead to an increase in porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) which can be detected in the urine
* Things that make diagnosis difficult: variable clinic course, lack of understanding about diagnostic process, and lack of a universal standard for test result interpretation

Patient Focus: Acute Intermittent Porphyria
* Most common porphyria
* Deficiency of hepatic PBG deaminase
* Autosomal dominant pattern with incomplete penetrance
* Affected individuals have a 50% reduction in erythrocyte PBG deaminase activity
* Latent prior to puberty
* Symptoms more common in females than males
* Increased urinary ALA & PBG

Prevalence in the General Population
Key Clinical Features
* Gastrointestinal symptoms - Abdominal pain (most common presenting complaint), nausea/vomiting, constipation, and diarrhea.
* Dehydration
* Hyponatremia
* Cardiovascular symptoms - tachycardia, hypertension, arrhythmias
* Neurologic manifestations - motor neuropathy, sensory neuropathy, mental symptoms, seizures.

Pathophysiology of the Acute Attack
Autonomic Nervous System
Peripheral Nervous System
Hypothalamus
Limbic area

Porphyrins excreted from liver
ALA crosses BBB
Causes oxidative damage
Accumulates in brain with neuronal and glial cell damage
Symptoms due to porphyrin
Precursor accumulation
Rather than deficiency of Heme
Porphyrins don’t Cross BBB
ALA induces liver
Damage via oxidative effects
Exacerbating Factors of Acute Attack
* Drugs that increase demand for hepatic heme (especially cytochrome P450 enzymes)
* Crash diets (decrease carbohydrate intake)
* Endogenous hormones (progesterone)
* Cigarette smoking (induces cytochrome P450)
* Metabolic stresses (infections, surgery, psychological stress)

Diagnosis of Acute Porphyria
Algorithm for Acute Porphyria Diagnosis
Treatment of the Acute Attack
* Hospitalization to control/treat acute symptoms:
o Seizures – Seizure precautions, medications?
o Electrolyte abnormalities
o Dehydration / hyponatremia
o Abdominal Pain – narcotic analgesics
o Nausea/vomiting – phenothiazines
o Tachycardia/hypertension – Beta blockers
o Urinary retention / ileus
* Withdraw all unsafe medications
* Monitor respiratory function, muscle strength, neurological status
* Mild attacks (no paresis or hyponatremia) – Intravenous 10% glucose at least 300 g per day
* Severe attacks – Intravenous hemin (3-4 mg/kg qdaily for 4 days) ASAP (can give IV glucose while waiting for IV hemin)
* Cimetidine for treatment of crisis and prevention of attacks

Hematin (Panhematin)
* Used in the treatment of the acute porphyrias since the 1970s
* Mechanism of Action: Reduces production of ALA / porphyrins by negative feedback inhibition on ALA synthetase
* Derived from outdated PRBCs from community blood banks
* Reconstitution of lyophilized hematin with 25% albumin recommended
o Reconstituted in sterile water originally –> less stable / degraded easily
o Degradation products cause an ↑ in adverse reactions
* Adverse reactions: Due to degradation products binding to endothelial cells, platelets, & coagulation factors
o Thrombophlebitis
o Anticoagulation (transient ↑ PT, bleeding may occur)
o Thrombocytopenia

* thrombophlebitis if given through large vein or central line
* Dosing:
o Acute attacks: 3-4 mg/kg/day x 4 or more days
o Max daily dose 6 mg/kg or 313 mg (1 vial) – even in obese patients
o Prevention of attacks: not well established; once or twice weekly infusions

A Study of Hemin Use in Clinical Practice

* Hemin approved under Orphan Drug Act of 1983
* Hemin removed from market in 2000 by FDA: 8/00-6/01
o Abbott Laboratories required to conduct open-label study of the safety of hemin manufactured at a new facility
o Largest trial / case series to date on hemin therapy
* Study design: “Real world” data about acute porphyria diagnosis, treatment & perceived efficacy of treatment
* Methods:
o Hemin only available through study participation – compassionate basis
o All pts judged to need hemin by their physicians were enrolled
o Confirmation of diagnosis not required
o Pts received hemin as normally prescribed by their physicians
o No specific outcome measures, exclusion criteria, or follow-up

Results of Hemin Used in Clinical Practice

* Study Population: 130 pts; 92% Caucasian; 72% female
* Precipitating factors: (40/130 pts): drugs (22%); hormonal (24%)
* Results:
o 111 pts treated for 305 acute attacks & 40 pts for prophylaxis
o Diagnostic lab findings reported in 53% (half with +results)
o Hemin regarded as effective for 73% of patients
+ Despite doses less than recommended in 20% of pts (< 3-4 mg/kg/day)
o Propylaxis with hemin in 1/3 of patients
+ Wide variability in prophylaxis regimens  lack of published guidelines
+ Among 31 receiving hemin prophylaxis for >1 month, 68% did not require subsequent tx for acute attacks
o 44% of pts experienced adverse events – most attributed to underlying disease and not hemin
+ Phlebitis was most common adverse event attributed to hematin

Long-Term Complications from Symptomatic Disease

* Neurological Sequelae
* Hypertension
* Renal failure
* Cirrhosis
* Hepatocellular carcinoma

Renal failure: Is hypertension the cause or the effect

* Debate about cause: Hypertension or another etiology?
* Increased risk of renal failure in those with more acute attacks
* Andersson et al  Population-based study (Sweden)
o Renal biopsies (n=16)  ischemic lesions, ? related to protracted vasospasm
o Theory of injury  Vasospasm from:
+ Porphyrin metabolites &
+ an upregulated SNS  ↑ urinary excretion of catecholamines during an acute attack
o By this theory, hypertension is not the sole cause of renal insufficiency

Hepatocellular Carcinoma (HCC)

* Estimated 60 to 70-fold ↑ risk of HCC in AIP patients
* Andersson  Retrospective population-based mortality study
o HCC  27% with AIP vs 0.2% deceased without AIP
o HCC more common in women (2:1)
o HCC more common in those with symptomatic disease
o Cirrhosis more common in AIP pts (12%) vs non-AIP (0.5%)
o Cirrhosis in AIP pts higher in W>M 3:1
* Retrospective analysis for genetic mutations in 17 pts with AIP & HCC (L Bjersing)
o Is PBGD a tumor suppressor gene? (No, 1 allele present in tumor)
o No mutations seen in p53 or ras (these mutations have been implicated in HCC caused by HBV or aflatoxin)
* De Siervi et al ALA is toxic to two hepatocellular cancer cell lines (HEP G2 & HEP 3B)
o Degree of cytotoxicity was directly related to concentration of ALA
o Adding hemin or D-glucose to ALA + cells decreased toxicity with HEP G2 cells
* Proposed Mechanism of cirrhosis / carcinogenesis:
o Reduced free heme pool  ↓ cytochrome P450 & antioxidant enzymes reactive oxygen species DNA damage
o ALA that accumulates can oxidize proteins & cause DNA damage

Prevention & Follow-up: Caring for Patients Between Attacks
* Avoidance of alcohol, smoking, and exacerbating drugs
* Adequate carbohydrate intake
* Medical alert bracelets/wallet cards
* Gonadotropin-releasing hormone analogues
* Iron overload from hemin (100 mg of hemin contains 8 mg of iron)
* Hepatocellular carcinoma screening
* End-Stage renal disease prevention
* Screening for Osteoporosis
o risk from GNRH analogues, immobility, malnutrition, & vitamin D deficiency

Prognosis
* Prior to 1970, fatality rates were 10% to 52%, now 10%
* Since introduction of hematin mortality has decreased
* Overall mortality in patients with acute attacks is 3-fold higher than the general population
* Delayed diagnosis and treatment contribute to higher mortality
Future Treatment Directions
* Liver transplantation
* Animal models used to mimic porphyrias with experiments to correct enzyme deficiency in tissues
* Non-viral mediated gene transfers
If You Were Asleep….Key Points to Remember
* Porphyrias are metabolic diseases resulting from a partial deficiency of an enzyme in the heme biosynthetic pathway
* Cause acute attacks secondary accumulation of heme precursors
* Clinical features: abdominal pain, tachycardia, hypertension, hyponatremia, seizures, motor neuropathy etc.
* Screen for porphyria with qualitative urinary PBG and if elevated measure quantitative urinary PBG and ALA
* Confirm diagnosis with urinary and fecal fractionated porphyrins and DNA testing
* Treat acute attacks with IV hemin
* Prevent acute attacks with smoking cessation, avoidance of inciting agents

References
Acute Intermittent Porphyria.ppt

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