There are four AHPs, Acute intermittent porphyria (AIP), Hereditary coproporphyria (HCP), Variegate porphyria (VP), and δ-aminolevulinic acid dehydratase porphyria (ADP), that cause acute neurovisceral symptoms. They are rare diseases, and due to this and the common symptoms with which they present, their diagnosis is often delayed. Sometimes by several years. The combined prevalence of these diseases is approximately 5 cases per 100,000 persons.
Treatment and Prognosis
The prognosis is usually good if the disease is recognized and if treatment is prompt, before severe nerve dysfunction 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, like hallucinations, may occur during attacks but are not chronic.
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 and water balance and to repletion of magnesium. Harmful drugs should be stopped.
For all patients with acute attacks who are sick enough to require hospital admission, hemin therapy should be started as quickly as possible. Hemin must be administered intravenously. Panhematin is the only hemin preparation available in the United States. Panhematin is more stable and less likely to produce phlebitis (a known possible side effect of hemin) 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. Although Panhematin® or Normosang have few side effects, they do act as mild anticoagulants. Thus, concurrent use of other anticoagulants such as heparin or Coumadin® (warfarin) should be avoided.
Harmful drugs, which can be identified using online drug databases, should be discontinued immediately.
Recurrent attacks related to the menstrual cycle can possibly be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent attacks can be prevented by prophylactic infusions of hemin, which are titrated to patient response. A newer alternative for prevention of frequent, recurrent acute attacks is the subcutaneous administration of givosiran (Givlaari).
Attacks can be prevented in many cases by avoiding known triggers including certain medications, alcohol, stress, smoking, illicit drugs, exogenous hormones and hypocaloric diet or fasting.
Patients with chronic kidney disease should have regular monitoring with a nephrologist. HCC surveillance with liver ultrasound or other imaging every 6 months, is recommended starting at the age of 50 years old for early detection. The risk of development of HCC is likely greater among patients with chronically elevated levels of ALA and PBG in serum and urine. Additionally, Hepatitis B and A vaccines are recommended to avoid preventable infections of the liver.
Liver transplantation has been shown to be an effective treatment for AIP patients with frequent and severe recurrent attacks who were resistant to conventional treatment including Panhematin®. However, experience with this treatment modality is still limited. It is anticipated that the need for liver transplantation for AHP will decrease now that givosiran has become available for use by at least some patients with frequent recurrent attacks. Givosiran (Givlaari) has proven effective in decreasing the frequency and severity of acute attacks, and it generally is reasonably well-tolerated.
Attacks can be prevented in many cases by avoiding alcohol excess, smoking, harmful drugs and dietary practices. Wearing a Medic Alert bracelet and carrying a Medic Alert card is advisable for patients who have had attacks, but is probably not warranted in most latent cases. Very frequent premenstrual attacks can possibly be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In some cases, frequent, cyclic attacks can be prevented by periodic (weekly, biweekly, etc.) infusions of hemin.
A newer alternative for prevention of frequent, recurrent acute attacks is the subcutaneous administration of givosiran (Givlaari). It is administered subcutaneously once per month, and it has generally been well-tolerated and highly effective. IV hemin can still be used, as may be required, in persons receiving givosiran.
Patients with severe renal disease tolerate hemodialysis or kidney transplantation. It is important that such patients still have adequate functional status at the time of kidney transplantation. Those with severe malnutrition and/or neurological deficits are at high risk of poor outcomes after 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.
Family Testing & Counseling
Because AIP is an autosomal dominant disorder, persons with disease-associated mutations in the HMBS gene have a 50% chance with each pregnancy of passing that mutation on to their offspring. The outlook for such offspring is generally good, since most individuals who inherit an HMBS gene mutation never develop symptoms of AIP.
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.
Treatment & Management
Acute attack symptoms, long-term complications, treatment and prognosis, and management are the same as AIP for VP and HCP patients. Avoidance of sunlight is recommended for all individuals diagnosed with HCP or VP who have blistering photosensitivity. Both VP and HCP patients can present with acute attacks alone, blistering skin symptoms alone, or both.
VP & HCP are both autosomal dominant and recommendations for familial testing are the same for AIP.
Overview & Symptoms
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 AHPs.
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.
Cutaneous porphyrias primarily affect the skin. Areas of skin exposed to the sun can have blistering or non-blistering symptoms and signs. Sun exposed skin can become fragile, and blistering complications can lead to infection, scarring, and changes in skin coloring (pigmentation). Cutaneous porphyrias include congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), porphyria cutanea tarda (PCT), and hepatoerythropoietic porphyria (HEP).
EPP is the most common porphyria in children with an estimated prevalence of 1 in 75,000 to 1 in 200,000 in the European population. The prevalence in the US is not known. 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.
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 has X-linked inheritance. This is identified as X-linked Protoporphyria (XLP). 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 solely by the liver and excreted in bile. Clinical and experimental studies have shown that this can impair bile formation and cause hepatobiliary injury, a condition called protoporphyric hepatopathy.
Treatment and Prognosis
Systematic reviews and abundant patient accounts show that drugs such as β-carotene (Lumitene) or cysteine show no evidence of efficacy.
Afamelanotide (Scenesse), an analogue of alpha-melanocyte stimulating hormone, administered as a subcutaneous biodegradable implant was FDA approved for the treatment of adults with EPP and XLP in 2019. MT-7117 is a novel orally administered melanocortin 1 receptor agonist, which is currently in Phase 3 clinical trials for EPP and XLP.
Protoporphyric liver failure can appear suddenly and progress rapidly. Liver function tests should be done annually. A rise in serum aminotransferases, alkaline phosphatase, or total bilirubin, without other explanation should be evaluated by additional serological and other testing, by liver imaging, and/ or biopsy for evidence of protoporphyric hepatopathy or other forms of incident liver disease, such as viral hepatitis, auto-immune liver disease, drug-induced liver disease, or others. Because of the increased prevalence of gall stones at early ages in EPP/XLP, it is important to assess for these and for evidence of extra-hepatic biliary obstruction. If the latter is found, it is important to correct the disease as promptly as possible, in order to minimize cholestatic liver disease, which is a major risk in EPP/XLP.
If after careful evaluation, the cause of the liver disease is determined to be protoporphyric hepatopathy, the treatment regimen for this generally involves a combination of plasmapheresis, blood transfusion, intravenous hemin, cholestyramine, vitamin E, and ursodeoxycholic acid. Exchange transfusions, designed to remove RBCs loaded with protoporphyrin, have also been successful as part of management. 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 (BMT) is potentially curative in both EPP and XLP and will prevent recurrent damage to the transplanted liver. BMT without prior liver transplantation may also be considered in carefully selected patients with severe EPP/XLP and with PP hepatopathy that is pre-cirrhotic. One may anticipate that successful BMT will, over time, lead to marked decrease in PP load and to gradual improvement in PP liver disease. However, BMT does carry with it major risks of adverse effects, including acute or chronic graft-vs-host disease.
Family Testing & Counseling
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.
First-degree family members are generally carriers. The recurrence risk of EPP in children of an affected individual depends on whether the partner carriers a FECH mutation or, more likely, the low expression allele.
Currently, in the USA, PCT has a prevalence of approximately 5 case for every 100,000 people. PCT develops when the activity of the uroporphyrinogen decarboxylase (UROD) enzyme becomes severely deficient (less than 20% of normal activity) in the liver. In most cases of PCT, patients do not have inherited UROD gene mutations and are said to have sporadic (or Type I) PCT (s-PCT). A UROD 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 UROD gene mutation from one parent, which has reduced the amount of UROD in all tissues. However, to develop PCT symptoms, other factors must be present to further reduce the UROD level in the liver to less than 20% of normal.
Excess iron, excess use of alcohol, use of oral estrogens, chronic hepatitis C, smoking, HIV infections, and mutations of the HFE gene (associated with the 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.
Treatment and Prognosis
Treatment seems to be equally effective in f-PCT and s-PCT. 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 [serum ferritin ~ 25-75 ng/mL], without development of anemia. Another treatment approach is a low dose regimen of the drug hydroxychloroquine, typically, 100 mg HCQ twice per week. 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. Chronic HCQ therapy has potential adverse effects, especially development of retinopathy; thus, baseline and at least annual and detailed eye examinations are recommended.
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 less effective in this setting.
CEP is one of the most severe porphyrias. Symptoms usually begin soon after birth or in early childhood. 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 UROS 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.