Disorders in Depth

1. Overview
   AIP is the most common of the AHPs, 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. 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 those of western European ancestry, the prevalence of such mutations is about 1/1700. 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.
2. 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 seen in women (~ 90% of symptomatic patients) in their child-bearing years (ages ~18-50 years). However, symptoms can also present in men. 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 someone has ever experienced. During acute 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—autonomic, peripheral, and central. Confusion, convulsions, and muscular weakness, due to impairment of the nerves controlling the muscles, may lead to paralysis. A full-blown acute attack usually gradually develops and escalates over hours and lasts for days or weeks. Recovery from severe paralysis is generally slow and often incomplete, with residual wrist drop or foot drop. 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. If the disease is already known or is diagnosed promptly early in the clinical course of an acute attack, both the severity and duration of the attack can be much diminished by prompt and appropriate treatment.
   1. Triggers
      Acute attacks are often provoked by drugs that induce hepatic cytochromes P-450, such as barbiturates, 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.
   2. Symptom Frequency
      Many patients with AHPs never experience acute attacks (called latent). They may go through their lives without adverse symptoms or signs. Such patients, if diagnosed at all, have the diagnosis made because of first-degree relatives with symptomatic disease that leads to family testing. Some patients have only a few attacks in their lifetimes, while others can have frequent attacks. Less than 4 attacks per year are classified as sporadic, while >4 per year are classified as recurrent.
3. Long-term Complications
   Risks for developing systemic arterial hypertension, chronic renal disease, and liver cancer (hepatocellular carcinoma) are increased in AIP. Anxiety and depression may be chronic issues in the AHPs.

4. 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).

5. Management
   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.

   1. 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 and oversee 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 AHP.
   2. 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. Only drugs and anesthetics classified as safe in the AHPs should be used. Acute attacks are treated with hemin; there is no evidence of adverse effects of hemin therapy on the mother or fetus. Little, if any, heme, bound to hemopexin or albumin in the serum, is taken up across the placenta into the developing fetus. Patients are prone to more frequent and severe attacks in the post-partum period, as well as during pregnancy. IV hemin can be given also to mothers who are breast-feeding, if required, without fear of adverse effects on their infants.

   3. Prevention
      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.

   4. 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.

   5. Emergency Room Support
      Coming soon—guidelines for ER physicians treating patients with confirmed AHP for acute attacks
6. Homozygous Form
   An ultra-rare form of homozygous AIP can occur when two HMBS mutations are present on both copies of the gene. This form is severe and presents in early childhood with neurological symptoms. Only a handful of cases have been reported.

References

1. Balwani M, et al. Acute hepatic porphyrias: Recommendations for evaluation and long-term management. 2017.
2. Bonkovsky HL, Dixon N, Rudnick S. Pathogenesis and clinical features of the acute hepatic porphyrias (AHPs). 2019

1. Overview & Symptoms
   1. VP
      VP is caused by mutations in the gene of the Protoporphyrinogen oxidase (PPOX) enzyme. Over most of the world, it is less common than AIP. In South Africa, however, a prevalence of 3 in 1,000 individuals has been estimated, most of the cases arising in Whites of Dutch ancestry. Acute attacks in VP are identical to those in AIP. 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.
   2. HCP
      The clinical presentation of HCP is similar to that of VP. About 10% develop blistering photosensitivity. The incidence of HCP appears to be at most 2 per 1,000,000. The deficient enzyme is coproporphyrinogen oxidase (CPOX).

2. 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.

1. 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.

2. Treatment & Management
   Treatment is the same as in the other AHPs. 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 hemin and hypertransfusions and hydroxycarbamide, the latter to decrease bone marrow overproduction of porphyrin precursors, was effective in another boy with ADP.
   1. Family Testing & Counseling
      ADP is the only AHP that is autosomal recessive. All children of an affected individual will be carriers of ADP, but are unlikely to develop any symptoms.

References

1. Neeleman et al. Clinical Remission of Delta-Aminolevulinic Acid Dehydratase Deficiency Through Suppression of Erythroid Heme Synthesis. 2019.

1. Overview
   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.

2. 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 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.
3. Long-term Complications
   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. They have features typical of iron deficiency, with low serum ferritins and transferrin saturations, even in the absence of apparent GI bleeding or other reasons for iron deficiency.

4. 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.

5. Management
   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.

   1. Prevention
      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. There is anecdotal evidence supporting improvement in severity of XLP with iron therapy. Iron supplementation may be considered for EPP patients who are symptomatic from iron deficiency and/or have hemoglobin levels <10 g/dL and a ferritin <10ug/L, with consideration of the individual patient’s risk of worsened photosensitivity versus benefit from iron supplementation. 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.

   2. 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.

References

1. Wensink D, et al. Liver involvement in patients with EPP. 2021.
2. Balwani M. Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. 2019.

1. Overview
   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.

2. 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.
3. Long-term Complications
   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.

4. 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.

5. Management
   1. Prevention
      Factors that tend to activate the disease (i. e., susceptibility factors above) should be removed. Sun protective clothing and avoidance may be necessary while someone is having active symptoms.
   2. Family Testing & Counseling Most cases of PCT are sporadic and will have no UROD mutations detected, for those with familial PCT the inheritance is autosomal dominant. With each pregnancy someone with f-PCT has a 50% chance of passing on the mutated UROD gene, however the penetrance is very low and if it is inherited it is unlikely symptoms will develop.

References

1. Singal AK. Porphyria Cutanea Tarda: Recent Update. 2019
2. Singal et al. Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. 2012

1. Overview
   CEP, also known as Günther disease, is very rare, with only several hundred cases reported in the world literature. The prevalence is not known, but probably is less than 1 in 1,000,000. It is due to the markedly deficient activity of the heme biosynthetic enzyme, uroporphyrinogen III synthase (UROS).

2. Symptoms
   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.

3. Long-term Complications
   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.
4. Treatment and Prognosis
   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. Recent results indicate that iron reduction therapy with phlebotomies lead to decreases in porphyrin levels and in severity of CEP.
5. Management
   Newborns with red-colored urine in their diapers should not undergo phototherapy for hyperbilirubinemia.
   1. Prevention
      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.
   2. Family Testing & Counseling
      CEP is an autosomal recessive disorder. Identifying the causative UROS mutations in a family enables prenatal and pre-implantation genetic diagnoses for at-risk pregnancies.

References:

1. Erwin A, Desnick RJ. Congenital Erythropoietic Porphyria: Recent Advances. 2019

1. Overview & Symptoms
   HEP is a very rare type of porphyria, due to mutations in both copies of the UROD gene resulting in severe deficiency of UROD enzyme activity in all cells, the same enzyme that causes PCT. 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. Sun protection is critical for management. HEP is an autosomal recessive disorder, all children of an affected individual will have familial PCT, but like likelihood of developing symptoms is low. The parents of a child with HEP will also have familial PCT.