Continuing Education Activity

Hepatic porphyrias are genetic disorders caused by the defect in an enzyme involved in heme synthesis and accumulation of heme precursors. Hepatic porphyrias include acute intermittent porphyria, variegate porphyria, aminolevulinic acid dehydratase deficiency porphyria, hereditary coproporphyria, and porphyria cutanea tarda. The acute hepatic porphyrias are manifest as neurological attacks (seizures, psychosis, severe abdominal and back pain, and acute polyneuropathy) and, to a lesser extent, with cutaneous manifestations such as photosensitive blistering rash or hypertrichosis. This activity reviews the pathophysiology, evaluation, and management of acute hepatic porphyrias and highlights the role of the interprofessional team in caring for patients affected by these conditions.

Objectives:

• Describe how a patient with acute hepatic porphyria might present.
• Outline how to evaluate a patient with suspected acute hepatic porphyria.
• Explain why it may be difficult to diagnose acute hepatic porphyria.
• Review why an interprofessional team that provides an integrated approach to the care of a patient with acute hepatic porphyria can help achieve the best possible outcomes.

Introduction

The porphyrias are a set of metabolic disorders, each representing a defect in one of the eight enzymes in the heme biosynthetic pathway that results in the accumulation of organic compounds called porphyrins. This leads to the clinical and biochemical profile typical for each porphyria.[1][2] Hepatic porphyrias are those in which the enzyme deficiency occurs in the liver. Hepatic porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD), hereditary coproporphyria (HCP), and porphyria cutanea tarda (PCT).

These conditions are distinct but have in common the accumulation of heme precursors. For acute porphyrias, which primarily affect the nervous system, the cause of symptoms seems to be the increased production of neurotoxic precursors. With chronic porphyrias, which primarily have skin manifestations, the cause of symptoms seems to be the buildup of photosensitizing porphyrins in the skin. Some types of porphyrias can have both neurological and cutaneous expressions. The treatment is the administration of intravenous hemin to prevent the progression of the symptoms. Liver transplantation (LT) is reserved for patients with life-threatening acute attacks or progression of symptoms despite hemin therapy.[2]

Etiology

Porphyrias are generally considered to be genetic diseases. Most types are caused by a mutation in a gene that produces heme and depends on which enzyme is deficient. The various porphyrias are inherited from an individual's parents and may be inherited in an autosomal dominant (AD) manner, an autosomal recessive (AR) manner, or an X-linked manner. For example, acute intermittent porphyria (AIP), variegate porphyria (VP), and hereditary coproporphyria (HCP) are AD conditions and affect men and women equally.[2] A fourth type, aminolevulinic acid dehydratase deficiency porphyria (ALAD), is an AR condition and is very rare.[2] For the three AD conditions, family studies with DNA analysis have demonstrated several mutations.[3][4][5] The underlying mechanism leads to a reduction in the amount of heme produced and an accumulation of heme precursors.[1] Furthermore, acute hepatic porphyrias can be triggered by a variety of drugs, many of which are thought to interact with liver enzymes involved in heme synthesis.

Epidemiology

In the United States, the prevalence of porphyria is approximated to be one in 25,000 individuals.[6] The worldwide prevalence is approximated to range from one in 500 to one in 50,000 individuals.[6] All racial and ethnic groups are affected by acute hepatic porphyrias. In most regions, AIP is the most common, and ALAD is the least common.[7] The prevalence of clinical AIP is reported to be 5 to 10 per 100,000 individuals, and the prevalence of genetic mutations of AIP is approximately one in 1675 individuals.[8] VP, which is rarer, has a reported prevalence of 4 to 13 cases per million individuals and a prevalence calculated to be approximately 3 symptomatic cases per million individuals. Of note, although AIP, VP, and HCP are AD disorders and thus, expected to affect men and women equally. However, AIP has demonstrated a female bias, with reports of attacks being five times more frequent in non-Hispanic females as compared with males.[9]

Pathophysiology

Porphyrins are the major precursors of heme, an important component of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes. In porphyrias, there is an absence of enzymes of the porphyrin pathway, causing abnormally elevated concentrations of these heme precursors, which are toxic to tissues at high levels.[2] These intermediates' chemical properties determine the site of buildup and, ultimately, the clinical manifestations. Physiologically, porphyrias can be classified as hepatic or erythropoietic based on whether these heme precursors first accumulate in the liver or the bone marrow and red blood cells, respectively. There are eight enzymes in the heme biosynthetic pathway, four of which are in the mitochondria and four of which are in the cytosol. Defects in any of these enzymes can lead to porphyria. The acute hepatic porphyrias are described by neurological attacks (seizures, psychosis, severe abdominal and back pain, and acute polyneuropathy) and, to a lesser extent, present with cutaneous manifestations, usually photosensitive blistering rash or hypertrichosis.

Histopathology

This can show subepidermal vesicles and marked thickening of superficial dermal vessels. There is minimal or no inflammation. In porphyria cutanea tarda, dermal papillae protrude into bulla with a festooned pattern. The roof of the blisters has eosinophilic, PAS+, and diastase-resistant linear globules.

History and Physical

Acute and chronic symptoms due to effects on the central and peripheral nervous system characterize acute hepatic porphyrias. The most common presenting symptom is neuropathic abdominal discomfort. The motor, sensory, and autonomic nervous systems are often affected, resulting in autonomic changes (e.g., tachycardia, hypertension), muscle weakness; sensory loss; and pain in the back, chest, and extremities. Unfortunately, physical findings are often minimal, and even severe symptoms may be discounted as a result. Abdominal pain with a relatively unremarkable physical examination is the most common neurovisceral manifestation of acute hepatic porphyria, the most common of which is AIP, and should warrant further evaluation. Identical symptoms may be seen in the other acute hepatic porphyrias: VP, HCP, and ALAD. VP and HCP may also present with blistering skin lesions.

Three groups of symptoms, abdominal pain, central nervous system abnormalities, and peripheral neuropathy, are described as a "classic triad" that should suggest acute porphyria. However, because they are highly nonspecific, they are often viewed as unrelated and not indicative of a unifying diagnosis.

Evaluation

Clinicians should gather a detailed history, perform a thorough physical examination, and follow up with the following investigations when they suspect acute hepatic porphyria.

1. Urine: Urine porphobilinogen (PBG) is the most important first-line screening test, which is both highly sensitive and highly specific. Through feedback, the reduced production of heme brings about elevated production of heme precursors, with PBG among the first substances in the porphyrin synthesis pathway.[10] In fact, in almost all cases of acute hepatic porphyrias, urinary PBG is significantly elevated.[11] Of note, repeat testing during an acute attack may be needed to diagnose a porphyria, as levels may be normal or almost normal between attacks. Up to 90% of genetic carriers of the more common, autosomal dominantly inherited acute hepatic porphyrias (AIP, VP, and HCP) have been discovered, in DNA tests, to be latent for classic symptoms and may need DNA or enzyme testing to make a diagnosis.
2. Plasma and feces for quantitative determination of ALA, PBG, and porphyrin levels
3. Decreased erythrocyte porphobilinogen deaminase (PBGD) activity is seen in approximately 90% of patients. It can also be seen in asymptomatic patients.
4. Basic metabolic panel: Hyponatremia is common. The probable mechanism includes the syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to central nervous system (CNS) involvement, gastrointestinal or renal sodium loss.
5. Liver function panel: mild elevation of transaminases is common, but other liver function tests generally remain normal

As acute hepatic porphyrias are very rare diseases, general hospital labs usually do not have the technology, the staff time, or the expertise to conduct testing for them. Commonly, such testing involves sending samples of blood, urine, and stool to a reference laboratory.[12]

Treatment / Management

The aim of treatment for an acute attack of hepatic porphyria is to abate the attack as quickly as possible and to provide appropriate supportive care and symptomatic care until the acute attack resolves. Hospitalization is usually required. Therapy requires confirmation that the patient indeed has acute porphyria, based on the finding of elevated urinary porphobilinogen (PBG), either at present or previously. Still, it does not require a diagnosis of the exact type of acute porphyria. In a patient known to have acute porphyria based on prior testing, the presence of an acute attack is largely established clinically.

Treatment of Acute Attack 

1. Intravenous hemin: For patients with an acute attack severe enough to require hospitalization, opioid analgesia, or other intravenous medication, or that is accompanied by nausea and vomiting, motor neuropathy, paresis, seizures, agitation, delirium, psychosis, ileus that prevents oral intake, or hyponatremia, intravenous administration of hemin is recommended.[10][11] This recommendation is based on the high risk of life-threatening sequelae from a severe acute porphyria attack and the clear efficacy and safety of hemin based on observational data; however, prospective randomized clinical trials are deficient.[13][14] Hemin should be administered immediately once an acute attack of hepatic porphyria is established. A typical regimen is hemin, 3 to 4 mg/kg reconstituted with 25% human albumin, administered intravenously as a single daily dose for four days.
2. Nutrition and hydration: Carbohydrate loading should be used to correct the fasting state and as a temporizing measure while waiting for an available dose of intravenous hemin.[2]
3. Hyponatremia: Can be severe in some patients and may require urgent intravenous hypertonic saline administration in symptomatic patients.
4. Seizure: Seizures occur in 10% to 20% of cases and can be controlled with a short-acting benzodiazepine, gabapentin, or magnesium. In patients with refractory seizures, anesthesia with propofol is safe.[15][16][17] 
5. Liver transplantation (LT) is reserved for patients with life-threatening acute attacks of AIP or progression of symptoms despite hemin therapy.

Management of Frequent Attacks

Though uncommon, frequent attacks may persist for many months or even a few years. This is common in women, with symptoms occurring monthly, 2 to 4 days before menstruation.[2] Ovulatory suppression with a gonadotropin-releasing hormone analog is helpful. Oral contraceptives are avoided because of their association with acute attacks in some users.[18] Prophylactic hemin infusions at intervals (weekly to monthly) provide reasonable control of symptoms. AIP patients with progressive neurological symptoms despite treatment, as mentioned earlier, should be evaluated for LT.

Differential Diagnosis

Given the non-specific presentations of acute hepatic porphyrias and their relatively low occurrence, patients may initially be suspected to have other, unrelated conditions. The major considerations in the differential diagnosis are other causes of abdominal pain; other causes of neuropathy, neuropsychiatric symptoms, or seizures; other causes of liver disease/abnormal liver function tests; and other porphyrias. Like acute hepatic porphyrias, these conditions can also present with nonspecific symptoms. For example, the polyneuropathy of acute porphyria may be misidentified as Guillain-Barré syndrome. The magnetic resonance imaging (MRI) findings can resemble those in posterior reversible encephalopathy syndrome (PRES), which points to the potentially substantial effects of acute porphyria on the central nervous system.[19] In these situations, testing for porphyria is recommended.

Prognosis

Due to the rarity and low penetrance of acute hepatic porphyrias, data is limited regarding the prognosis of individuals with the condition. Mortality is increased in patients with severe clinical manifestations.[20] However, individuals with mild clinical phenotypes may never be diagnosed, leading to an erroneous overestimation of mortality. Patients can have a good prognosis, especially if their disease remains latent, with prompt diagnosis and treatment of acute attacks.

Complications

A major complication of acute hepatic porphyrias is an acute attack, which can be life-threatening if not treated urgently.[2] This episodic crisis is characterized by abdominal pain frequently accompanied by nausea and vomiting, hypertensive crisis, and tachycardia. The most severe episodes involve neurological manifestations, frequently, motor neuropathy, which causes muscle weakness and potentially quadriplegia as well as central nervous system symptoms, such as seizures and coma. There may be brief psychiatric symptoms infrequently, such as anxiety, confusion, hallucinations, and overt psychosis. Once the acute attack passes, all of these symptoms usually resolve.

Furthermore, patients are at risk for developing hypertension, chronic renal failure, hepatocellular carcinoma, and iron deficiency anemia from menstrual blood loss (just as in women without porphyrias) or iron overload from frequent hemin therapy. Therefore, hypertension should be controlled, nephrotoxic medications should be avoided, patients over 50 years of age should have imaging of the liver performed for early detection of hepatocellular carcinoma, and serum ferritin levels should be monitored.

Deterrence and Patient Education

Decreasing or eradicating exacerbating factors can play an important role in treating acute attacks of hepatic porphyrias and in preventing future attacks. Some patients have predictable triggers for acute attacks; these should be avoided or reduced as much as possible.

During an acute attack, potentially harmful medications should be discontinued whenever possible. It is strongly advised for clinicians to consult the websites of the American Porphyria Foundation and the European Porphyria Network (EPNET), which list many medications, including those that are not classified with certainty; provide evidence for these classifications, and are regularly updated. Also, these websites should be consulted to avoid prescribing harmful medications in treating concurrent illnesses or symptoms.

Potentially harmful lifestyle factors include smoking and alcohol use. Patients should be counseled to avoid or discontinue smoking, including the use of marijuana, and to avoid alcohol intake. Smoking and alcohol use can both exacerbate acute hepatic porphyrias via induction of hepatic cytochrome P450 enzymes (CYPs), which, in turn, can diminish the pool of hepatic heme and directly induce enzymes in the porphyrin pathway, leading to increased synthesis of toxic heme precursors.

Acute attacks are also associated with sex hormones (e.g., progesterone), decreased caloric or carbohydrate intake (especially fasting), and metabolic stress due to infections or other illnesses.

Enhancing Healthcare Team Outcomes

Once a patient recovers from an acute attack, an effort should be made to identify the inciting factors that contributed to the attack and to advise him/her to avoid those exacerbating factors. Thus, an interprofessional team approach is an ideal way to limit this complication. For example, a physician and pharmacist can provide a list of medications to avoid – available on the websites of the American Porphyria Foundation and the European Porphyria Network – and reinforce to the patient to avoid smoking and drinking alcohol, known exacerbating factors of acute hepatic porphyrias. Furthermore, a dietitian can counsel the patient regarding what to eat to lower the risk of future attacks, for example, maintaining a healthy, well-balanced diet that is fairly high in carbohydrate content, such as foods including bread, pasta, fruits, starchy vegetables, and dairy products. When faced with a female patient whose attacks are related to monthly hormonal changes, an obstetrician-gynecologist or a primary care provider can prescribe treatment to help with this too, such as a gonadotropin-releasing hormone (GnRH) analog to suppress ovulation. A pharmacist should always be involved to provide medication reconciliation and to make sure the combination of medications will not lead to an exacerbation. Working with the clinical team and providing guidance for appropriate therapy. A specialty-trained nurse is usually in the best position to assist with patient and family education and coordinate follow-up care. Keeping the team apprised of untoward developments or when the patient is non-compliant.  In severe cases, if a patient has had repeated attacks and hemin has not helped, referral for evaluation for liver transplantation may be an option. Thus, an interprofessional team of specialists that provides an integrated approach to the care of these patients can help to achieve the best possible outcomes. [Level 5]