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Treatment For Acute Hepatic Porphyria

Scenesse For Erythropoietic Protoporphyria

Caring for Patients with Acute Hepatic Porphyria

SCENESSE® is a prescription medication that contains the active substance afamelanotide. Afamelanotide is used to increase tolerance to the sun and light in adults with a confirmed diagnosis of erythropoietic protoporphyria .

SCENESSE® acts by increasing the levels of eumelanin in the skin, shielding against UV radiation and visible light, including sunlight. Afamelanotide is a synthetic form of a hormone called alpha-melanocyte stimulating hormone . Afamelanotide works in a way similar to the natural hormone, by making skin cells produce eumelanin which is a brown-black type of melanin pigment in the skin. By increasing the amount of eumelanin and acting as an antioxidant, SCENESSE® can help to reduce the sensitivity of the skin to sunlight and artificial UV light sources.

Implant is given subcutaneously by a trained health care professional.

Acute Hepatic Porphyria: Pathophysiological Basis Of Neuromuscular Manifestations

  • Division of Neuromuscular Diseases, Department of Neurology and Neurosurgery, Federal University of São Paulo , São Paulo, Brazil

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options.

What Are Some Symptoms Of Ahp

AHP can cause a wide range of symptoms that mimic those of other diseases, and some people with a defective gene associated with AHP may not have any symptoms whatsoever. People with AHP who experience symptoms can suffer from severe attacks that are often unpredictable and include very painful abdominal pain. Some people may also experience chronic symptoms such as pain in between attacks. Most people have at least one other symptom in addition to the belly pain. Some of these symptoms may include:

  • Nausea and vomiting
  • Skin blistering

The various symptoms of AHP can lead to physical and emotional suffering and exhaustion. This can affect every aspect of life, including overall physical comfort the ability to work consistently and maintaining a healthy level of social connectedness with others.

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Givlaari For Acute Porphyria

GIVLAARI is a treatment used to reduce acute hepatic porphyria attacks in adults. There are 4 types of AHP: acute intermittent porphyria , variegate porphyria , hereditary coproporphyria , and ALA-dehydratase deficient porphyria . GIVLAARI is given once a month as a subcutaneous injection by a healthcare professional.

GIVLAARI is a double-stranded small interfering RNA therapeutic specifically targeting ALAS1 mRNA, reducing ALAS1 mRNA levels and leading to reductions in urinary ALA and PBG.1

ALA, delta-aminolevulinic acid ALAS1, delta-aminolevulinic acid synthase 1 mRNA, messenger RNA PBG, porphobilinogen

Key Clinical Trial Results For Givosiran For Prevention Of Acute Porphyric Attacks

Acute porphyrias

A Phase I trial was performed to investigate the safety, pharmacokinetic, pharmacodynamic, and efficacy of givosiran in confirmed AIP patients.7 This trial enrolled a total of 40 patients with mutation-confirmed AIP. Parts A and B of the trial investigated patients without attacks in the past 6 months . Part A of the trial investigated selected dosages of givosiran, given as a single subcutaneous injection, while part B investigated once-monthly injections for two injections. Higher doses of givosiran were associated with lower expression of urinary ALA and PBG levels. Part C of the trial investigated patients with recurrent attacks at two different dosages and dosing frequencies . The 5.0 mg/kg once-monthly group led to the greatest reduction in ALAS1 mRNA level at 74 ± 6%. The placebo groups in this study were administered sterile normal saline.

A phase I/II open-label extension study of givosiran enrolled all patients from phase I part C.65 The study had a mean intervention duration of 22.8 months, and up to 30.9 months of total treatment. The results of the OLE study demonstrated maintenance of clinical activity with continuous monthly dosing of givosiran at 2.5 mg/kg. There was consistent reduction of urinary ALA and PBG by 80% at 12 months and > 85% at 18 months. The mean annualized attack rate was reduced by 96% and annualized hemin use was reduced by 98%. Continued givosiran dosing maintained the reduced of mean attack rate in patients out to 30 months.

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Most Common Symptoms Of Acute Hepatic Porphyria

People with AHP can experience gastrointestinal, neurologic, psychiatric, cardiovascular, or skin symptoms. The most common symptom is abdominal pain which can be severe and last several hours.

Those with AHP can also experience chronic symptoms. These are symptoms that last a long time and may include:

  • fatigue- feeling overly tired or having low energy
  • nausea- feeling of sickness in the abdomen, stomach, chest, or head with feeling an urge to vomit
  • pain physical discomfort and/or suffering in the body

Our Approach To Hepatic Porphyria

UCSF’s dedicated team of hepatologists delivers cutting-edge, compassionate care for all kinds of liver disorders, including hepatic porphyria. Treatment for hepatic porphyria focuses on avoiding triggers such as alcohol consumption or too much iron in the body that lead to symptoms.

Patients with excess iron may need to have set amounts of blood withdrawn at regular intervals. Over time, this lowers iron to normal levels and decreases symptoms such as sun sensitivity.

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Clinical Manifestations Of Acute Hepatic Porphyrias

The most dramatic manifestations of AHPs are acute neurovisceral attacks, which often require hospitalization and, in the severest cases, a critical care setting . As highlighted in the case study, the most common symptom in AHPs is severe, diffuse abdominal pain other signs and symptoms can include nausea, weakness, tachycardia, hyponatremia, mental status changes, hypertension and changes in urine colour . If the attack is particularly severe, treatment is not initiated promptly or exposure to triggers is prolonged, patients can also experience seizures, delirium and paralysis, posterior reversible encephalopathy syndrome along with permanent neurological damage or fatality .

Fig. 2

Constellation of clinical characteristics and associated conditions for acute hepatic porphyria. a Only occurs in severe attacks. b Only occurs in variegate porphyria and hereditary coproporphyria. ANS: autonomic nervous system CNS: central nervous system PNS: peripheral nervous system HCC: hepatocellular carcinoma CKD: chronic kidney disease. Created with BioRender.com

The Acute Porphyric Attack

Acute Hepatic Porphyria: Disease Diagnosis and Revelations Regarding the Role of siRNA Therapy

The symptoms and signs of attacks are nonspecific and can mimic many other disease processes. Constipation, fatigue, mental status changes , and insomnia typically precede an acute attack. The most common symptoms of an attack are

Abdominal pain may be excruciating and is disproportionate to abdominal tenderness or other physical signs. Abdominal manifestations may result from effects on visceral nerves. Usually, there is no inflammation, the abdomen is not tender, and there are no peritoneal signs.

Motor involvement during acute attacks may lead to persistent muscle weakness and muscle atrophy between attacks. Cirrhosis, hepatocellular carcinoma, systemic arterial hypertension, and renal impairment become more common after middle age in acute intermittent porphyria and possibly also in variegate porphyria and hereditary coproporphyria, especially in patients with previous porphyric attacks .

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Classification Of The Porphyrias

Traditionally, the porphyrias have been classified as either hepatic or erythropoietic depending on the primary site of overproduction and accumulation of porphyrin precursors or porphyrins, although some porphyrias have overlapping features., The hepatic porphyrias are characterized by overproduction and initial accumulation of the porphyrin precursors, ALA and PBG, and/or porphyrins primarily in the liver, whereas in the erythropoietic porphyrias, overproduction and initial accumulation of the pathway intermediates occur primarily in bone marrow erythroid cells. Here, for simplicity, we have classified the 8 major porphyrias into 3 groups: the 4 acute hepatic porphyrias, the single hepatic cutaneous porphyria PCT, and the 3 erythropoietic cutaneous porphyrias . It should be appreciated that there is some overlap, as patients with the acute hepatic porphyrias, hereditary coproporphyria , and variegate porphyria may have cutaneous lesions, and the rare homozygous dominant forms of acute intermittent porphyria , HCP, and VP, as well as the rare homozygous recessive form of PCT, hepatoerythropoietic porphyria, have erythropoietic manifestations.

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How To Manage An Acute Hepatic Porphyria Attack

Managing Acute hepatic porphyria is dependent on managing triggers. During an attack, it is important to seek treatment and pain relief.

During an Acute hepatic porphyria attack, in some people, hospitalization is necessary and heme is given intravenously. In a few others, hospital visits would not be required.

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What Are Porphyrias And How Do They Differ

Altogether there are seven main types of porphyria which are usually classified by what type of illness they cause

  • There are four acute porphyrias: acute intermittent porphyria , variegate porphyria and hereditary coproporphyria and a very rare porphyria called ALA dehydratase deficiency porphyria. They are called acute because they usually cause sudden attacks of severe stomach pain that last for several days. VP and HC may also cause skin symptoms.
  • The other porphyrias, porphyria cutanea tarda , erythropoietic protoporphyria and the rare congenital erythropoietic porphyria affect mainly the skin and do not cause acute symptoms in other organs.

The porphyrias may also be classified as hepatic or erythropoietic depending on the organ where the porphyrins accumulate, the liver for the hepatic porphyrias , the bone marrow for the erythropoietic porphyrias.

My Fight To Receive Outpatient Treatment For Acute Hepatic Porphyria

Acute Hepatic Porphyria Treatment Guidelines

Columnist Claire Richmond shares her journey with Panhematin infusions

I was once in the hospital during the holiday season. At that time, I could only receive Panhematin infusions for an acute porphyria attack as an inpatient. I plugged my grandmas ceramic, tabletop tree in next to the bedside, where its rainbow of colored lights shone brightly. I received a port during that stay, surgically implanted in my chest below my right collarbone.

A month later, I was in a similar attack state and a different hospital room, just down the hall. It was my 34th birthday, and I took my port for a test drive. I stayed for just three days that time, but I knew all the nurses by then.

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Lifestyle And Home Remedies

If you have porphyria:

  • Learn what could trigger symptoms. Talk to your doctor about the type of porphyria you have and become familiar with possible symptom triggers and ways to avoid them.
  • Inform your health care providers. Tell all your health care providers that you have porphyria. This is particularly important because sometimes treatments, medications or surgery can trigger porphyria symptoms.
  • Wear a medical alert bracelet or necklace. Have information about your condition inscribed on a medical alert bracelet or necklace, and always wear it.

What Causes Ahp And How Does It Affect The Liver

Porphyrins are compounds needed to produce heme. Heme is vital to the body and responsible for breaking down medications and other substances.

AHP occurs when there is a problem with heme production in the liver. When heme is not produced properly, certain toxins called PBG and ALA accumulate in the liver and can further circulate throughout the body. ALA and PBG are associated with the painful attacks and other disease manifestations people with AHP experience.

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Is Acute Hepatic Porphyria Preventable

You cant prevent inheriting the disease, but you may be able to prevent symptoms from occurring by avoiding triggers. If youve never had an attack, you should avoid all possible triggers. If youve had attacks and have isolated the triggers that caused them, you may only need to avoid certain ones. Common triggers include:

Medications:

Symptoms And Signs Of Acute Porphyrias

Acute Hepatic Porphyria: Overview and Emerging Therapies

Symptoms and signs of acute porphyrias involve the nervous system, abdomen, or both . Attacks develop over hours or days and can last up to several weeks. Most gene carriers experience no, or only a few, attacks during their lifetime. Others experience recurrent symptoms. In some women, recurrent attacks often coincide with the luteal phase of the menstrual cycle.

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How Is Acute Hepatic Porphyria Treated

Treatment for AHP is focused on preventing and managing symptom attacks. During an attack, you may need hospital care. You may need various medications to reduce your different symptoms. Between attacks, you may need different medications to keep your triggers in check. Treatment is more effective when you and your healthcare provider are able to identify which triggers affect you the most.

Treatment for an acute attack may include:

  • Hemin injection. During a severe attack, a doctor may give you hemin through an injection into your vein to help reduce the porphyrins in your blood. Hemin is a salt derived from red blood cells that inhibits porphyrin production in your body.
  • Pain relief. You may need strong pain relievers, such as opioids, during an acute attack.
  • Phenothiazines. These drugs can control severe nausea and vomiting.
  • IV fluids and nutrition. Symptoms such as abdominal pain, nausea, vomiting, diarrhea and constipation may deprive your body of calories and hydration during an attack. AHP can also cause deficiencies in sodium and magnesium. You may receive IV fluids containing carbohydrates and electrolytes.
  • Seizure medications. Up to 20% of people may need treatment for seizures during an attack.

Long-term treatment options may include:

Heme Precursor Patterns In Acute Porphyria And Genetic Diagnosis

shows the profile of heme precursors in urine or feces for the four hepatic porphyrias. The pattern is distinctive for each type, reflecting the step that is genetically altered. The route of precursor excretion reflects the relative lipophilicity of the individual precursors, as noted above. Before the advent of genetic analysis, the enzymatic defect for each of the porphyrias was predicted from these patterns and confirmed by assays of enzyme activity. In AIP, the altered gene product, HMBS , exists in two forms, which arise by alternative splicing of the primary transcript the erythroid HMBS gene transcript lacks exon 2 of the hepatic transcript. Because the enzyme is cytosolic, it persists in erythrocytes. A commercial blood test was developed, which is used together with urine tests to diagnose AIP. Its main shortcoming is partial overlap of the normal and deficient ranges. Also, it yields a false-negative result when the HMBS mutation is in exon 2, which the erythroid-specific transcript lacks. Finally, sample handling problems may allow decay of the activity and a false-positive result. Overall, the HMBS assay identifies about 80% of AIP carriers. Enzyme tests for HCP and VP , respectively, are not available commercially. An assay for CPOX in whole blood was offered in the 1990s but resulted in many false-positive results and ultimately was discontinued.

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Treatment Of Acute Hepatic Porphyria

Mostly preventive measures are taken to stop Acute hepatic porphyria attacks and improve the quality of life. A synthetic version of heme i.e. hemin is prescribed. It helps in making hemoglobin proteins.

Depending on the condition of the patient the doctor recommends the following:

  • Glucose Supplements: These are given orally or intravenously. They help the body to have enough glucose to make red blood cells.
  • Gonadotropin-Releasing Hormone Agonist: This is prescribed to females as they lose heme during menstruation.
  • Phlebotomy: It is a blood removal procedure that helps get rid of the excessive amount of iron in the blood.
  • Gene therapies: Givosiran that is approved by the FDA is given in gene therapies. It is determined that givosiran decreases the rate of production of toxic by-products in the liver, lessening the acute hepatic porphyria attacks.

Regular testing is required during the treatment of Acute hepatic porphyria, to help assess the progress. Measurement of heme, iron, and other elements is important to determine whether the treatment is working or some adjustments need to be made in the treatment plan.

More clinical trials are being conducted to identify and develop new treatments to help manage this condition.

Clinical Overview Of Acute Hepatic Porphyrias

Pathophysiology, Pharmacology and Treatment of Acute Intermittent ...

Nowadays, the AHP are considered a chronic condition with a negative impact on physical and emotional health, leading to low quality of life and complicated by acute attacks, which typically present with multiple dysfunctions of autonomic, peripheral, and central nervous system, requiring hospitalization and not rarely with fatal outcomes . In addition, long-term complications including liver disease , systemic arterial hypertension, and chronic kidney disease are part of the natural history of AHP .

Typically, most patients with AHP are women between second and fifth decades of life with recurrent episodes of severe abdominal pain accompanied by malaise, fatigue, psychiatric disturbances , nausea and vomiting, loss of appetite and constipation, and tachycardia . Even subtle neurological symptoms lasting hours to days often require visits to emergency department and opioid prescriptions to pain relief . The dark-colored urine, the clinical feature that derives the term porphyrus, may be unremarkable because ALA and PBG are colorless and is most observed after exposure of the voided urine to light, leading to the oxidative reaction of porphobilinogen to uroporphyrin and porphobilin .

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Panhematin For Acute Porphyria

Panhematin® is a treatment for the acute Porphyrias manufactured by Recordati Rare Diseases in Lebanon New Jersey. It is a lyophilized form of alkaline heme that has to be reconstituted immediately prior to administration. Panhematin® should be infused into a large peripheral vein. A large central line or port may be used, if available.

Doctors administer Panhematin® to correct heme deficiency in the liver and repress production of porphyrin precursors. Panhematin® almost always normalizes porphyrin and porphyrin precursor values. Three to four mg/kg of Panhematin® given once daily for four days early in an attack produces a highly beneficial effect in most patients. Commonly noted are decreases in pulse rate, blood pressure, abdominal pain, as well as decreased levels of urinary porphobilinogen . These effects can occur within a day.

Panhematin® is the only commercially available heme therapy in the United States. While a high carbohydrate diet is recommended for patients with Porphyria, it is not regarded as highly effective by itself. Intravenous glucose therapy is a treatment option for mild attacks. When heme therapy was introduced as a treatment, it was recommended that it be initiated only after several days of glucose therapy was unsuccessful.

Today, physicians experienced in treating patients with attacks of Porphyria recommend early use of Panhematin® rather than waiting to see if glucose alone will be of decisive help.

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