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Porphyria refers to a group of nine hereditary metabolic disorders caused by defects in the heme biosynthesis pathway. They result from reduced activity of specific enzymes in the pathway causing accumulation of toxic metabolites of heme. These rare conditions are of physiatric interest due to possible presentation with limb pain, generalized weakness and/or axonal neuropathy.


All porphyrias are inherited diseases with the exception of most cases of porphyria cutanea tarda (PCT) which requires triggers such as hepatic infection or dysfunction, often in addition to genetic predisposition. Inheritance may be autosomal dominant, autosomal recessive with either a homozygous or compound heterozygous mutations, or X-linked with variable expression in females in the case of protoporphyria. Hundreds of mutations have been identified and clinical manifestation is typically associated with 50% or more reduction of enzyme function. Episodes may be brought on by various environmental factors. 

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 rarer with prevalence estimates of 1 in 1,000,000 and others with less than 10 cases described in medical literature. All ethnic and racial groups can be affected, prevalence is higher in females and most patients present after puberty.

Risk factors besides the genetic mutations include environmental factors promoting phenotypic expression include alcohol intake, smoking, hepatitis C virus or HIV infections, some medications, 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, urinary retention or incontinence, paresis, seizures and focal neurologic deficits may be seen in the initial stages. Acute psychiatric manifestations including anxiety, agitation, altered mental status, depression, hallucinations, and acute psychosis can be seen in up 80% of acute attacks. 


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. Precipitating factors should be assessed such as stress, caloric restriction, medications, or cyclic hormonal changes.

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

Gene panels, which are increasingly available. and enzyme activity level analysis of the heme biosynthetic enzymes are definitive and specific laboratory studies. Metabolite detection is also commonly used. Porphobilinogen (PBG), a porphyrin precursor, and delta-aminolevulinic acid (ALA) are porphyrin precursors that can be detected in urine. Porphyrins (uroporphyrin, coproporphyrin, and protoporphyrin) can be detected in urine, blood, or stool. Elevated urine porphobilinogen (PBG) identifies nearly 100 percent of AIP patients during an acute attack and 90 percent of disease carriers at baseline as it is both highly specific and sensitive. PBG can be measured in the serum if a patient has advanced renal disease, however, this is less sensitive. Serum electrolytes and thyroid function tests should be done to evaluate for associated hyponatremia and hyperthyroidism. Other tests that are recommended as part of the work-up include hepatitis C antibodies, HIV antibodies, and the presence of the HFE gene due to their implication in the potential pathogenesis of PCT.


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

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 may help establish a diagnosis. Nerve conduction studies 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 those of sensory nerves. Electromyography needle examination may show signs of denervation with abnormal insertional and resting activity, decreased recruitment, and abnormal motor unit action potentials. These findings typically 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. Full recovery from acute episodes is possible. Severe anemia, respiratory compromise, irreversible neuronal damage, as well as hepatocellular carcinoma and paraneoplastic syndromes can occur 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

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, especially if neurological and psychiatric symptoms are also involved.

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, administration of intravenous hemin (known previously as hematin which describes the chemical reaction product of hemin and sodium carbonate solution), phlebotomy, iron chelation, chloroquine, hydroxyurea, beta carotene for cutaneous manifestations, cholestyramine to reduce enterohepatic recycling, stem cell or liver transplantation, and bone marrow transplant for erythropoetic porphyria.

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.

Some patients develop cyclic attacks related to their menstrual cycle in which case adjusting their hormonal contraceptive to low dose, considering gonadotropin releasing-hormone (GnRH) analogue or prophylactic hemin infusions can be helpful in prevention. As a last line of therapy, orthotopic liver transplantation has been curative in patients with intractable attacks refractory to hemin therapy.

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 hemin. 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 multi-disciplinary communication between hematology, oncology, gastroenterology, genetic counseling, neurology and rehabilitation teams is important for continuity of care. This 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

There do not appear to be any functional outcomes scales specific to the porphyrias. FIM score for inpatient rehabilitation, tests of ambulatory functional status such as Timed Up and Go, 6-minute walk or others, and Mini-Mental Status Exam (MMSE) or other preferred evaluation tool for cognition could all be appropriate.

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

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

Further research evaluating onset of symptoms and electrophysiological changes may be beneficial as well. Earlier consideration for liver transplant which could be beneficial and may end the acute attacks is an option. RNA interference therapy with small interfering RNAs (siRNAs) that target ALAS1 have been studied in mouse models of acute intermittent porphyria and have been shown to decrease plasma ALA and PBG levels within 8 hours, more rapidly and effectively than a single hemin infusion. Clinical trials are in progress.

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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Original Version of the Topic

Travis Coats, MD, Andreea Nitu-Marquise, MD. Porphyria.7/21/2021

Author Disclosures

Ramza Malik, DO
Nothing to Disclose

Andreea Nitu-Marquise, MD
Nothing to Disclose