For Healthcare Professionals: Disorders In-Depth

AIP is the most common of the acute porphyrias, with a world-wide prevalence of clinically manifest, symptomatic disease of approximately 5-10 per 100,000. AIP results from autosomal dominant inheritance of a mutation in the gene for the enzyme hydroxymethylbilane-synthase (HMBS), which is also known as porphobilinogen deaminase (PBGD) or uroporphyrinogen I synthase. Recent evidence both from Europe and the USA indicates that potential disease-causing mutations in the HMBS gene are far more common than previously believed; in western Europeans and European-Americans, the prevalence of such mutations is about 1/1700 [Nordmann et al, 1997, J Intern Med; Chen et al, 2016, Hum Mutat]. These observations emphasize that the enzyme deficiency alone is not sufficient to produce the symptoms of AIP; other factors, such as gender, menarche/puberty, drugs, hormones, excess alcohol use, smoking, dietary factors, and/or other genetic factors are also important. Sometimes, triggering factors cannot be identified.

Symptoms

Most people who have a potential disease-causing mutation in the HMBS gene never develop symptoms; this is referred to as “latent” AIP. Symptoms rarely develop prior to puberty, and the clinical disease is mainly a disease of women in their child-bearing years [ages ~18-50 years]. Acute attacks almost always start with pain in the abdomen but sometimes in the chest, back, or thighs, and are often accompanied by nausea, vomiting, and constipation. The severity of the pain typically escalates over a few hours; it may become very severe and be described as the worst pain women have ever experienced, more severe than the pain of childbirth. During moderate to severe attacks, heart rate and blood pressure are commonly increased. These symptoms and signs are all due to the effects of the disease on the nervous system. Confusion, convulsions, and muscular weakness, due to impairment of the nerves controlling the muscles, may lead to paralysis. An acute attack usually lasts for days or weeks. Recovery from severe paralysis is generally slow and often incomplete, with residual wrist drop or foot drop.

Acute attacks are often provoked by drugs such as barbiturates, sulfonamide antibiotics, anti-seizure drugs [barbiturates, hydantoins, valproate], rifampin, metoclopramide, and excess alcohol. Attacks in women may occur after ovulation and during the second half [luteal phase] of the menstrual cycle when progesterone levels are high. Reduced food intake, often in an effort to lose weight, as well as infections, surgery, and stressful situations may also precipitate attacks. Risks for developing chronic renal disease and liver cancer (hepatocellular carcinoma) are increased in AIP. The skin is not affected, except in some AIP patients who have developed kidney failure, in whom plasma levels of uroporphyrin may increase due to impaired renal clearance.

Diagnosis

The finding of a substantial increase of porphobilinogen (PBG) in urine establishes that one of the three most common acute porphyrias (AIP, HCP or VP) is present. Therefore, measuring PBG and creatinine concentrations in a random urine, obtained while the woman is having abdominal pain, is the most important test for diagnosing acute porphyria, especially in an acutely ill patient. Because concentrations of PBG in the urine depend in part upon how dilute the urine is, they are best expressed normalized to urinary creatinine concentrations [mg PBG/ g creat or mmol PBG/mol creatinine]. Deficiency of HMBS activity in red blood cells helps to establish the diagnosis of AIP. However, normal HMBS activity in red blood cells does not exclude AIP because ~10% of patients harbor a mutation that is not expressed in erythrocytic HMBS, but only in hepatic HMBS. A diagnosis of AIP is established in a patient by DNA studies, which demonstrate a disease associated HMBS gene mutation in almost all cases.

Many different mutations have been identified in the HMBS gene. Almost every family with AIP has a different mutation in this gene. Within one family, however, everyone who inherits a deficiency of HMBS has the same mutation. Knowing the mutation that causes AIP in a particular family member means that others who carry the mutation can be reliably identified and counseled to avoid excess alcohol, drugs, dietary practices, etc. that may trigger symptoms. Measuring red blood cell HMBS activity has been useful in family studies but is less accurate than DNA analysis.

Treatment and Prognosis

The prognosis is usually good if the disease is recognized and if treatment is prompt, before severe nerve dysfunction or death develops. Although acute symptoms usually resolve after an attack, repair of nerve damage and associated muscle weakness may require several months or longer. Mental symptoms may occur during attacks but are not chronic. Premenstrual attacks often resolve quickly with the onset of menses.

Hospitalization is often necessary for acute attacks. Medications for pain, nausea, and vomiting and close observation are generally required. Hyponatremia, sometimes severe, with serum Na < 125 mEq/L, and hypomagnesemia are not uncommon during acute attacks. During treatment of an attack, attention should be given to sodium (salt) and water balance and to repletion of magnesium. Harmful drugs should be stopped.

Attacks are treated with glucose loading and hemin. These are specific treatments that lower activity of hepatic ALA synthase-1, the first and normally rate-controlling enzyme of the heme biosynthetic pathway. Marked up-regulation of hepatic ALA synthase-1 is the hallmark of acute porphyric attacks, regardless of which gene farther down the pathway is deficient in activity. Glucose or other metabolizable carbohydrates down-regulate hepatic ALA synthase-1. This has been called the ‘glucose effect’ or ‘carbohydrate repression’ of ALA synthase-1. Dextrose and more complex carbohydrates are given by mouth if possible. However, women with moderate to severe acute attacks usually have nausea, vomiting, and anorexia and are unable to eat sufficient quantities of dextrose or other nutrients. Therefore, these often must be administered by vein. Intravenous glucose is usually given as a 10% solution, at least three liters daily. Administration of 300 g of dextrose per day via a pediatric feeding [Dobhoff-type] tube can also be used, if there is adequate gut motility.

However, unless an attack is mild, it is now common practice to begin treatment with hemin, which is more effective than glucose loading. Hemin therapy can be started after a trial of glucose therapy, but the response to hemin therapy is best if started early in an attack. For all patients with acute porphyric attacks who are sick enough to require hospital admission, we recommend institution of IV heme therapy as quickly as possible.

Hemin must be administered intravenously. Panhematin®, from Recordati Rare Chemicals [Milan, IT], is the only hemin preparation available in the United States. Panhematin® is more stable and less likely to produce phlebitis (an inflammation of the vein; a known possible side effect of hemin therapy) if it is reconstituted in human serum albumin before it is given. Because of the high frequency of thrombophlebitis, Panhematin is best given into a large-bore, high-flow central vein, such as a subclavian vein, either by PICC line or by a central port. Normosang, which is heme arginate, is available in most European and some other countries around the world. It, too, is now supplied by Recordati Rare Chemicals, and it, too, seems less prone to cause thrombophleibitis or other adverse effects if it is mixed with human serum albumin and administered into a central vein.

Diet

Individuals with AIP who are prone to attacks should eat a normal or high carbohydrate diet and should not greatly restrict their intake of carbohydrate and calories, even for short periods of time. If weight loss is desired, it is advisable to consult a physician and a dietitian to have them prescribe an individualized diet that is not more than 20% below the normal level of calories for the patient. This should result in a gradual weight loss and usually will not cause an attack of porphyria. Gastric bypass surgery for obesity has occasionally led to first attacks of acute hepatic porphyria.

Pregnancy

Pregnancy is usually well tolerated, but the hormonal changes may exacerbate AIP in some women. Proper nutrition and hydration are important during pregnancy and labor, after delivery, and for the duration of breastfeeding. As always, only drugs and anesthetics classified as safe in porphyria should be used. Acute attacks are treated with glucose or hemin; there is no evidence of adverse effects of hemin therapy on the mother or fetus. Patients are prone to more frequent and severe attacks in the post-partum period, as well as during pregnancy. IV heme can be given also to mothers who are breast-feeding, if required, without fear of adverse effects on their infants.

Prevention

Attacks can be prevented in many cases by avoiding harmful drugs and unwise dietary practices. Wearing a Medic Alert bracelet is advisable for patients who have had attacks, but is probably not warranted in most latent cases. Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent, cyclic attacks can be prevented by once weekly infusions of hemin.

An attractive alternative for prevention of frequent, recurrent acute attacks is the subcutaneous administration of givosiran [Givlaari, Alnylam Pharma, Cambridge, MA]. Givosiran is an siRNA specifically directed against hepatic ALA synthase-1, which has proven remarkably effective in decreasing the numbers of recurrent acute attacks [Sardh et al, 2019, NEJM; Balwani et al, 2020, NEJM]. It is administered once per month, and it has generally been well-tolerated and highly effective. IV heme and high glucose intakes can still be used, as may be required, in persons receiving givosiran. Patients with severe renal disease tolerate hemodialysis or kidney transplantation. Liver transplantation has been very effective for patients with classical AIP who have repeated attacks and who are resistant to other treatments. However, experience with transplantation as a treatment for AIP is still limited, and it seems likely that the availability of givosiran will decrease the numbers of patients with AIP who need liver transplantation. Unfortunately, the very rare patients, mostly young children, with biallelic and severe deficiencies of HMBS activity, have not been helped by liver transplantation.

Because AIP is an autosomal dominant disorder, a person with a mutation in his or her HMB-synthase gene has a 50% chance with each pregnancy of passing that mutation on to his/her offspring. The outlook for such offspring is generally good, since most individuals who inherit an HMBS gene mutation never become ill or have only a few attacks.

HCP is an autosomal dominant acute porphyria with a clinical presentation similar to that of AIP, except that some patients (about 10%) develop blistering photosensitivity. The incidence of HCP appears to be at most two per 1,000,000. The deficient enzyme is coproporphyrinogen oxidase (CPOX). Urinary ALA and PBG are increased, especially during acute attacks, but generally to a lesser degree than in AIP. The diagnostic finding is a definite increase in urine PBG/creatinine and coproporphyrin, with a copro III/I isomer ratio >1.5. Plasma porphyrin levels are usually normal but may be increased in patients with skin lesions. Elevation of urine coproporphyrin only is not diagnostic, because it occurs in a number of other medical conditions, notably in heavy users of alcohol and/or liver disease. Elevation of ALA and coproporphyrin (with normal PBG) is typical of lead poisoning, which should be confirmed with a blood test for heavy metals (lead, mercury, arsenic). A marked elevation in fecal coproporphyrin III is suggestive of HCP, but should be confirmed by analysis of DNA for a disease-causing CPOX mutation. Treatment, complications, and preventive measures for HCP are the same as for AIP.

VP is caused by one of several mutations in the enzyme protoporphyinogen oxidase (PPOX). Over most of the world, it is less common than AIP. In South Africa, however, a prevalence of three in 1,000 individuals has been estimated, most of the cases arising in whites of Dutch ancestry. The PPOX mutation in this group has been traced to a couple who were among the original Dutch immigrants to the Cape of Good Hope in the late 17th century. Acute attacks in VP are identical to those in AIP, and their management and prevention are the same. Blistering skin lesions are much more common than in HCP, are indistinguishable from those of PCT and may be chronic. There is no remedy for VP photosensitivity other than use of protective clothing. Unlike PCT, iron-depletion and chloroquine are not helpful. Urine ALA and PBG are increased during attacks, but as in HCP, these may increase to a lesser degree and decrease more rapidly than in AIP. Plasma porphyrins are frequently increased in VP, in contrast to AIP and HCP, and the plasma of VP patients displays a distinctive fluorescence peak at 626 nm [following excitation at 410 nm], which is unique and diagnostic. Fecal porphyrins are also elevated and are predominantly coproporphyrin III and protoporphyrin. Long term complications are the same as in AIP.

ADP is the least common of all the porphyrias with fewer than 10 cases documented to date. This is an autosomal recessive disease, whereas the other three acute porphyrias are autosomal dominant. All of the reported cases have been males, in contrast to the other acute porphyrias.

A severe deficiency of the enzyme δ-aminolevulinic acid dehydratase (ALAD) causes an increase of 5-aminolevulinic acid (ALA) in the liver, other tissues, blood plasma, and urine. In addition, urine coproporphyrin and erythrocyte protoporphyrin are increased. Treatment is the same as in the other acute porphyrias. Liver transplantation alone has not been of great benefit in the one patient with ADP so treated, but a recent report from Holland indicated that IV heme and hypertransfusions and hydroxycarbamide, the latter to decrease bone marrow overproduction of porphyrin precursors, was effective in another boy with ADP [Neeleman et al, 2019, Hepatology].

Porphyria cutanea tarda (PCT) is the most common type of porphyria, with a prevalence of approximately one case for every 20,000 people. PCT develops when the activity of the enzyme, involved in synthesis of heme, uroporphyrinogen decarboxylase (URO-decarboxylase) becomes severely deficient (less than 20% of normal activity) in the liver. In most cases of PCT, patients do not have inherited URO-decarboxylase gene mutations and are said to have sporadic (or Type I) PCT (s-PCT). A URO-decarboxylase inhibitor generated only in the liver accounts for the severely deficient enzyme activity in s-PCT. Approximately 20 percent of cases have familial (or Type II) PCT (f-PCT). Such individuals have inherited a URO-decarboxylase gene mutation from one parent, which has reduced the amount of URO-decarboxylase in all tissues from birth. However, to develop PCT symptoms, other factors must be present to further reduce URO-decarboxylase level in the liver to less than 20% of normal. Such f-PCT patients may develop blisters at an early age or have relatives with the disease. Excess iron, excess use of alcohol, use of oral estrogens, chronic hepatitis C, smoking, HIV (human immunodeficiency virus) infections, and mutations of the HFE gene (associated with the disease hemochromatosis) where excess iron accumulates in the liver have all shown to play a role in development of PCT. Other susceptibility factors may exist but have yet to be identified.

Symptoms

In PCT the skin blisters develop on sun-exposed areas of the body, such as the hands, feet and face. The skin in these areas may blister or peel after minor trauma. Increased hair growth, as well as darkening and thickening of the skin may also occur. Neurological and abdominal symptoms are not characteristic of PCT.

Liver function abnormalities are common, but are usually mild. PCT is often associated with hepatitis C infection, which also can cause these liver complications. However, liver tests are generally abnormal even in PCT patients without hepatitis C infection. Progression to cirrhosis and even liver cancer occurs in some patients.

Diagnosis

The diagnosis of PCT is made by demonstrating abnormally high concentrations of porphyrins in urine or plasma, with a predominance of uroporphyrin and heptacarboxylporphyrin. Porphobilinogen (PBG) is normal and aminolevulinic acid (ALA) may be slightly elevated. Fecal porphyrins may be normal or somewhat elevated, with a predominance of isocoproporphyrin. Patients with f-PCT usually have no family history of the disease because the penetrance of the disease is low. Patients with f-PCT can be distinguished from patients with s-PCT by finding half-normal URO-decarboxylase activity in cells, or preferably by confirming an altered gene sequence using DNA studies. In all patients, it is important to look for all known susceptibility factors, as susceptibility factors should be eliminated or minimized as part of the management plan.

Treatment and Prognosis

PCT is the most treatable of the porphyrias. Treatment seems to be equally effective in f-PCT and s-PCT. Factors that tend to activate the disease (i. e., susceptibility factors above) should be removed. The most widely recommended treatment is a schedule of repeated phlebotomies (removal of blood), with the aim of reducing iron in the liver. The target of this treatment is a serum ferritin near the lower limit of normal. Another treatment approach is a low dose regimen of the drug hydroxychloroquine. This drug mobilizes porphyrins from the liver. There is some risk of liver injury when PCT is treated with hydroxychloroquine, but this adverse effect is minimized by treating with a low-dose regimen. Relapses that occur after the initial treatment can be treated successfully using the same approach as for initial treatment.

PCT caused by hepatitis C can be treated with one of the antiviral regimens to remove that specific risk factor. Patients with marked iron overload should be treated by phlebotomy rather than hydroxychloroquine, to correct both the PCT and the underlying iron overload. PCT is often more severe and difficult to treat in patients with end-stage renal disease. Iron supplements should be stopped and erythropoietin administered to support small volume phlebotomies to reduce the serum ferritin level. Hydroxychloroquine is not effective in this setting.

Hepatoerythropoietic porphyria (HEP) is a very rare type of autosomal recessive porphyria, due to mutations in both copies of the UROD gene resulting in severe deficiency of UROD enzyme activity in all cells. The main manifestation of HEP is skin blistering and is more severe than that observed in PCT. The blistering begins in infancy and resembles other severe cutaneous porphyrias such as CEP. However, the porphyrin profile in plasma and urine is similar to what is seen in PCT. The diagnosis is confirmed by checking UROD activity level in red blood cells and by genetic testing.

Congenital erythropoietic porphyria (CEP), also known as Gunther disease, is very rare, with only several hundred cases reported in the world literature. The prevalence is not known, but probably is less than one in 1,000,000. It is an autosomal recessive disorder due to the markedly deficient activity of the heme biosynthetic enzyme, uroporphyrinogen III synthase (URO-synthase). Multiple mutations in the URO-synthase gene that produces this enzyme have been identified in different families.

Symptoms

CEP is one of the most severe porphyrias. As is characteristic of the erythropoietic porphyrias, symptoms usually begin soon after birth or in early childhood. Newborns with red-colored urine in their diapers should not undergo phototherapy for hyperbilirubinemia. Some severe cases have been diagnosed prenatally with hemolytic anemia and non-immune fetal hydrops. Severe early-onset patients typically become transfusion-dependent secondary to hemolytic anemia and ineffective erythropoiesis, and have extreme photosensitivity. Less severe patients, who have more residual URO-synthase enzymatic activity, may not be transfusion-dependent, but will have cutaneous photosensitivity. Adult-onset cases may occur due to myelodysplasia.

The cutaneous photosensitivity results in severe blistering and, following their rupture, can lead scarring and to secondary infections of the skin and bone. Photomutilation can result in the loss of facial features (nose, ear and lids) and digits. Hypertrichosis on sun-exposed skin, reddish-brown colored teeth (erythrodontia), and reddish-colored urine are common features. There may be bone fragility due to expansion of the bone marrow and vitamin D deficiency. In severe causes, erythrocytes have a shortened life-span, and mild or severe hemolytic anemia results, along with increased erythroid synthesis and splenomegaly.

Diagnosis

Clinical diagnosis is based on anemia, transfusion-dependence, and remarkable cutaneous photosensitivity, manifested by blistering lesions on sun-exposed skin. Porphyrins accumulate first in the bone marrow, are deposited in the teeth and bones, and are markedly increased in erythrocytes, plasma, urine, and feces. The porphyrin metabolites, uroporphyrin I and coproporphyrin I, are markedly evaluated in erythrocytes, plasma, and urine. Coproporphyrin I is strikingly increased in feces. In some milder cases, zinc protoporphyrin may be elevated in erythrocytes. Identifying the mutations by sequencing of the URO-synthase gene confirms the diagnosis and can predict severity. Very rarely CEP is due to a mutation in the X-linked GATA1 gene. Identifying the causative URO-synthase mutations in a family enables prenatal and pre-implantation genetic diagnoses for at-risk pregnancies.

Treatment and Prognosis

Avoidance of sunlight is most important in the management of CEP. Protective clothing is a must, and special tinted glass on house and car windows is strongly recommended. Chronic erythrocyte transfusions to maintain a hematocrit of >35% are required in severe transfusion-dependent cases to reduce porphyrin production by the marrow. In transfusion-dependent patients, bone marrow transplantation may be considered as this is a curative treatment for severely affected CEP patients.

Erythropoietic protoporphyria (EPP) is the most common porphyria in children with an estimated prevalence of one in 75,000 to one in 200,000 in the European population. Most cases are caused by the markedly reduced activity (<30% of normal), of ferrochelatase, the last enzyme in the heme biosynthetic pathway which catalyzes the insertion of iron into protoporphyrin to form heme. Deficiency of ferrochelatase results in the accumulation of protoporphyrin which is highly photoactive leading to the clinical symptoms. The inheritance of EPP is autosomal recessive. In about 90% of cases, a loss of function mutation in the (FECH) gene is inherited on one allele with a common low expression genetic variant IVS3-48C on the other. This common genetic variant is only disease causing in the presence of a pathogenic FECH mutation in trans. The frequency of this low expression allele in the FECH gene varies by population. It is present in about 43% of Japanese, 31% of Southeast Asians, 10% of Caucasians, and 1 to 3% of African Americans. Alternatively, about 5% of patients inherit two loss of function FECH mutations

In 2-10% of cases, the clinical symptoms of EPP are caused by a gain of function mutation in erythroid specific δ-aminolevulinate synthase-2 (ALAS2) gene, which is x-linked inheritance. As a result, the bone marrow produces more protoporphyrin than is needed for hemoglobin synthesis. In both EPP and XLP, protoporphyrin accumulates in the marrow and is transported to the skin in the plasma and red blood cells, where it initiates a photosensitivity reaction when the skin is exposed to sunlight. Protoporphyrin is not excreted by the kidneys, but is taken up by the liver and excreted in bile. Clinical and experimental studies have shown that this can impair bile formation and cause hepatobiliary injury.

Symptoms

Photosensitivity begins in early childhood, and can be difficult to diagnose, since there is usually no skin blistering or physical findings on exam. Photosensitivity can present within minutes of exposure to sunlight with severe burning pain on the sun exposed areas of the skin (generally the dorsum of the hands, feet and face). These episodes of pain may last for 2–3 days, and are usually unresponsive to any analgesics. The pain may be accompanied by localized swelling and erythema of the affected areas depending on the length of sunlight exposure. Patients are also sensitive to sunlight that passes through window glass (long wave ultraviolet light, or UVA). These symptoms greatly impair quality of life and limit employment opportunities and life style. Large amounts of protoporphyrin in bile can cause a formation of gallstones rich in this porphyrin. Approximately 28% of patients have abnormal liver enzymes, and 1-5% have severe hepatobiliary injury from protoporphyrin toxicity that may necessitate liver transplantation. About 40% of patients have anemia which is usually mild and microcytic.

Diagnosis

The diagnosis of EPP/XLP is established biochemically by demonstrating increased protoporphyrin in red blood cells, with a predominance of metal-free protoporphyrin rather than zinc protoporphyrin. In XLP, the fraction of zinc protoporphyrin is higher than in EPP, ~10-40% of the total amount of protoporphyrin. The test is called “Erythrocyte Protoporphyin” in many labs, and a fractionation of free and zinc protoporphyrins may need to be specified. Plasma porphyrins are also increased in most cases. It is important to send these tests to a lab proficient in testing to get accurate results. Measurement of urine porphyrins is not helpful for biochemical diagnosis of EPP/XLP.

Treatment and Prognosis

Systematic reviews show that drugs such as β-carotene (Lumitene) or cysteine show no evidence of efficacy. Most patients learn to avoid sunlight as much as possible. Patients should be routinely screened for iron and vitamin D deficiencies and started on supplementation if clinically indicated. To avoid preventable injuries to the liver, Hepatitis A and B vaccinations are recommended, as is the avoidance of excessive alcohol use and other potential hepatotoxins.

Protoporphyric liver failure can appear suddenly and progress rapidly. Liver function tests should be done annually. A rise in transaminases without other explanation should be evaluated by liver imaging or biopsy for evidence of protoporphyrin hepatopathy. The treatment regimen for this generally involves a combination of plasmapheresis, blood transfusion, intravenous hemin, cholestyramine, vitamin E, and ursodeoxycholic acid. Levels of porphyrins in plasma and red blood cells should be followed closely during treatment. Liver transplantation is sometimes necessary, but it remains difficult to predict which patients will develop liver failure. Bone marrow transplantation is potentially curative in both EPP and XLP and will prevent recurrent damage to the transplanted liver.

Afamelanotide (Scenesse), an alpha-melanocyte stimulating analogue, administered as a subcutaneous biodegradable implant was FDA approved for the treatment of adults with EPP and XLP in 2019. MT 7117 is an novel orally administered melanocortin 1 receptor agonist which is currently in Phase 3 clinical trial for EPP and XLP.