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Porphyria is a term referring to a group of nine hereditary metabolic disorders that are caused by a defect in the heme biosynthesis pathway. These disorders are all the result of reduced activity of a particular enzyme in that pathway resulting in the accumulation of toxic metabolites of heme.


All porphyrias are inherited diseases with the exception of porphyria cutanea tarda (PCT). Typically, inheritance is autosomal dominant where a homozygous or compound heterozygous states might be incompatible with life.  For the autosomal recessive inheritance only the homozygous or compound heterozygous states will cause disease.  X-linked protoporphyria has an X-linked inheritance pattern.

Epidemiology including risk factors and primary prevention

It is estimated that less than 200,000 individuals in the United States are affected by a variety of porphyria. The individual prevalence of subtypes of porphyria varies dramatically. PCT is the most common and has prevalence of 1 in 10,000, whereas acute intermittent porphyria (AIP), has prevalence of 1 in 20,000. Other forms of acute porphyrias are more rare with prevalence estimates of 1 in 1,000,000 and others with less than 10 cases described in medical literature.

Risk factors include genetic mutations encoding for the various enzymes of the heme biosynthetic pathway. Environmental factors promoting phenotypic expression include: alcohol intake, smoking, hepatitis C virus infection, and exogenous estrogen usage.


A deficiency any of the last seven enzymes in the heme biosynthesis will cause a specific type of porphyria.  Mutations of the first enzyme in the pathway, Aminolevulinic acid synthase-2 (ALA) will cause sideroblastic anemia rather than porphyria. Clinical manifestations occur due to the accumulation of toxic metabolites that are not processed.

Cutaneous manifestations occur as pophyrins are transported via plasma to the skin where they act as photosensitizers. Hepatotoxicity may be precipitated by deposition of protoporphyrin crystals in hepatocytes and bile canaliculi, promoting interference with redox mechanisms in the liver which promotes the production of cytotoxic bile.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time):

New onset/acute

A history of unexplained abdominal pain, current severe pain particularly in the abdomen and without peritoneal signs, cutaneous manifestations, nausea, vomiting, tachycardia, hypertension, anxiety, agitation with development of acute psychosis possible, and focal neurologic deficits may be seen in the initial stages.


These individuals may develop worsening confusion, hallucinations, and seizures. Neuropathy may proceed to tetraparesis and diminished respiratory ability due to weakness. Cutaneous manifestations may remain for weeks to months after initial onset.


Patients are typically asymptomatic between exacerbations provided their weakness and neuropathy have resolved or they have not developed an associated malignancy.

Specific secondary or associated conditions and complications

Metabolic and hormonal derangements such as hyponatremia, thyrotoxicosis, and exaggerated estrogen response may be seen in the acute phases of illness. Peripheral neuropathy may progress to a myelopathic picture with respiratory depression that necessitates mechanical ventilation. Vision threatening complications can occur such as corneal perforation and scleromalacia perforans.

Essentials of Assessment


The most common presenting symptom of acute porphyria is abdominal pain in the left lower quadrant lasting for hours to days.  Nausea and vomiting are commonly described.

Patients will describe diffuse weakness or severe weakness in the limbs that mimics tetraparesis. Anxiety, mood disturbances, or altered mental status occasionally follow focal neurologic complaints.

Physical examination

Vital signs often reveal tachycardia, fever, and hypertension during acute attacks.

Cutaneous porphyrias typically manifest with bullous skin fragility or non-bullous acute photosensitivity and may lead to facial scarring, epidermal atrophy, or pseudoscleroderma. Non-cutaneous porphyrias may exhibit jaundice or erythema with rare occurrence of vesicles or skin fragility.

Neurologic examination may reveal confusion, focal or diffuse weakness, ataxia, diminished light touch, sharp/dull discrimination, and vibrioception. Motor weakness is typically more pronounced than sensory changes.

Visual examination of the patient’s urine may be red to brown in natural light and pink to red under fluorescent light.

Presence of localized abdominal tenderness, peritoneal signs, vaginal discharge, cervical motion tenderness, or genitourinary tract bleeding should point away from a diagnosis of porphyria.

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Functional assessment of a patient with acute exacerbation of porphyria will be highly variable. Some have limited functional decline while others experience tetraparesis, cognitive deficits, or psychosis. Pain is a very common symptom and may interfere with functional status and the ability for self-care.

Laboratory studies

Genome and enzyme activity level analysis of heme biosynthetic enzymes are considered gold standard. Detection of elevated urine porphobilingen identifies nearly 100 percent of AIP patients during an acute attack and 90 percent of disease carriers at baseline. Urine porphyrin studies to evaluate for water soluble heme precursor metabolites and stool porphyrin studies for fat soluble metabolites. Serum electrolytes and thyroid function tests to evaluate for associated hyponatremia and hyperthyroidism.


Imaging findings in the work up of porphyria are largely non-specific.

Use of computed tomography (CT) scan of the abdomen and pelvis assists in the process of ruling out other causes of abdominal pain that commonly accompanies porphyria exacerbation.

Magnetic resonance imaging (MRI) of AIP patients may show white-matter, high intensity lesions in the brain. Patients who had these findings were noted to have bilateral lesions, often bioccipital. Diffuse cerebral atrophy is often seen, however, case reports suggest a preponderance of frontal lobe involvement.

MRI of the liver may exhibit areas of high intensity signal with signs of fat saturation.

Supplemental assessment tools

Nerve conduction studies of patients may show abnormalities of sensory nerve and compound motor action potentials with changes in nerve excitability patterns in symptomatic patients. Motor nerve conduction velocities are typically decreased more than sensory nerve velocities. Electromyography needle examination may show signs of denervation with abnormal insertional activity and resting activity, decreased recruitment, and abnormal motor unit action potentials. These findings together suggest a primarily axonal lesion with subsequent myelin damage rather than a primary demyelinating process.

Peripheral nerve histopathology is consistent with axonal neuropathy and secondary demyelination. Brain histopathology may show vacuolization of neurons and focal demyelination.

Early prediction of outcomes

Early detection and treatment of porphyria is important as both the acute phases of illness and long term sequelae may be fatal or profoundly debilitating. Severe anemia, respiratory compromise, potentially irreversible neuronal damage, as well as hepatocellular carcinoma and paraneoplastic syndromes are possible with late diagnosis and poorly managed illness.


Exogenous estrogen use, alcohol, smoking, low carbohydrate diets or fasting, and a variety of CYP 450 metabolized medications have been implicated in promoting symptoms. Physician assistance should be provided for individuals who are attempting to lose weight as they may trigger an acute illness episode

Social role and social support system

Individuals diagnosed with porphyria may be dependent upon friends or family due to pain, mobility, or cognitive deficits. Friends and family should also partner with health care professionals and the patient to address lifestyle modifications to lessen the impact of disease. Encouragement through the treatment process will improve compliance.

Professional issues

Consider the fact that many patients who are diagnosed with porphyria have undergone a long history of unexplained symptoms that were dismissed by those unfamiliar with the clinical presentation. Severe abdominal pain responding to opioids causes frequent emergency department visits and may lead to distrust of the physician-patient relationship.

Rehabilitation Management and Treatments

Available or current treatment guidelines

General recommendations include: avoidance of precipitating factors, powerful sunscreens, genetic testing of relatives, and evaluation of associated conditions such as hepatocellular carcinoma.

Other strategies include: carbohydrate consumption to decrease porphyrin synthesis, intravenous hematin administration, phlebotomy, iron chelation, chloroquine, hydroxyurea, beta carotene for cutaneous manifestations, cholestyramine to reduce enterohepatic recycling, and stem cell or liver transplantation.

Pain management achieved with parenteral narcotics for acute exacerbation with celiac plexus blocks being an interventional pain management option. Long term narcotics are rarely needed.

Implementation of a rehabilitation program involving physical, occupational, and speech therapy disciplines is helpful to return patients to their baseline functional status.

At different disease stages

Acute phase: Acute exacerbation of porphyria may be a medical emergency so clinicians should achieve a diagnosis early. Oral or intravenous dextrose should be given to decrease porphyrin synthesis followed by intravenous hematin. Respiratory status must be observed for potential compromise requiring mechanical ventilation. Careful monitoring of electrolytes is necessary with repletion of any deficiencies.  Parenteral narcotics are helpful for the severe pain that is often associated with the initial stages of disease.

Subacute phase: After initial stabilization, intravenous medications can be discontinued and the pain will likely be controlled by oral medications and dietary modifications to promote carbohydrates. If the patient continues to experience intractable abdominal pain, then celiac plexus blocks may be beneficial to decrease narcotic usage. Measures should be undertaken to prevent further attacks as outlined above. Patients should be evaluated by rehabilitation professionals to institute a goal oriented scheme for functional restoration and development of a home management plan.

Chronic/stable phases: Strict adherence to preventive measures should be continued by patients and their families. Oral medications may supplement environmental exposure control. Continued rehabilitation is beneficial in those experiencing continued neurologic deficits. Long term pain management is usually not required.

Coordination of care

Open communication between acute care medical professionals and rehabilitation staff is important for continuity of care. An interdisciplinary team approach is necessary for management of psychiatric symptoms, nutrition modification, medication management, advancing strengthening exercises, environmental changes, and the eventual transition to a home environment.

Patient & family education

Patients and their families must be educated about warning signs of acute disease exacerbation and prophylactic strategies. These include: medication reconciliation regarding safe and unsafe drugs, prompt treatment of infections, normocaloric diet to avoid fasting, alcohol and smoking avoidance, reduction of UV light exposure, use of sunscreen, and general stress management strategies such as exercise or mindfulness techniques.

Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally-based

FIM score will be used in inpatient rehabilitation to measure the progress. Ambulatory functional status may be assessed with The Timed Up and Go Test or another deemed appropriate by the individual practitioner. Cognitive status may be monitored with a Mini-Mental Status Exam (MMSE) or another preferred evaluation tool.

Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Early evaluation by multidisciplinary rehabilitation personnel is encouraged given the long course of illness and recovery. Patients with significant neurologic manifestations and continued need for medical supervision will benefit from inpatient rehabilitation.

Involvement of the patient’s family and support structures is vital as disease prevention plays a significant role in overall disease management. Encouragement of environment modulation and prevention techniques represents an effective tool for clinicians.

Adequate treatment of painful episodes in the acute and subacute phases may represent an avenue for establishment of the doctor-patient relationship. While somatic pain should resolve after the initial stages of the illness and rehabilitation, neuropathic pain may remain and cause significant functional disturbances.

Cutting edge/emerging and unique concepts and practice

Cutting edge concepts and practice

Genetic analysis is increasingly available to assist with porphyria subtype diagnosis. A further stratification of symptoms, treatments, and rehabilitation strategies may develop for the specific subtypes.

Electrodiagnostic studies remain a helpful tool in patients with a neuropathic presentation. Given the relatively unique findings of an axonal motor neuropathy, early electrodiagnostic studies should be pursued to help establish a diagnosis. Further research evaluating onset of symptoms and electrophysiological changes may be beneficial to these patients.

Some reports suggested that a liver transplant could be beneficial and end the acute attacks.

Gaps in the evidence-based knowledge

Controversies and gaps in the evidence-based knowledge

Prevention techniques are commonly employed to minimize the frequency and severity of disease exacerbations; however, the efficacy of these techniques is not well established in the literature.

Rehabilitation techniques and outcomes for these patients is currently lacking outside of scattered case reports. Further studies would be warranted given neurologic complications.


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