Refsum Disease and the Hepatic Porphyrias (Diseases of Tetrapyrrole Metabolism)
Updated: December 9, 2025
Background
The aberrant metabolism of big tetrapyrrole molecules causes remissions and exacerbations in the rare inherited neurodegenerative diseases known as hepatic porphyrias and Refsum disease.
The prosthetic group of hemoglobin, heme, and the photosynthetic pigment chlorophyll and are two typical examples of big tetrapyrrole molecules.
The phytol a massive hydrocarbon alcoholic substituent on chlorophyll is a notable exception to the rule that side groups on both species involve very tiny organic groups.
Foods and medications that raise the levels of the relevant biological toxin, which might cause or prolong an exacerbation, must be avoided by patients in both disease groups.
The iron-containing tetrapyrrole heme is necessary for a various of biological processes including oxidative metabolism, gas transport, and xenobiotic detoxification.
A collection of metabolic diseases known as porphyrias are caused by defects in one of the eight enzymes in the heme biosynthesis pathway, which leads to the buildup of organic substances known as porphyrins.
Epidemiology
Even though refsum sickness is uncommon, heterozygote carriers who consume a lot of beef and dairy products may be at risk.
Approximately 1 in 100,000 people are thought to have acute intermittent porphyria (AIP), the most prevalent form of acute hepatic porphyria (AHP).
Neurologic dysfunction is characterized by remissions and exacerbations in both Refsum disease and hepatic porphyrias. These might resolve entirely or show progressive deterioration.
Porphyrias and Refsum sickness are more common in those with Caucasian ancestry. The exception is Porphyria cutanea tarda, which is observed among Black people with Bantu ancestry.
Acute intermittent porphyria in females and porphyria cutanea tarda in males may have more symptomatic attacks, although autosomal inheritance should ensure similar prevalence in both sexes.
Anatomy
Pathophysiology
Phytanic acid, the neurotoxic in Refsum disease, is accumulated in the brain and visceral parenchyma of those who have it due to a lack of phytanic acid alpha-hydroxylase.
Either direct absorption of phytol from ruminant fat in meat or milk or conversion of ingested phytol are the sources of phytanic acid.
The enzyme deficiencies associated with hepatic porphyrias are usually inherited in an autosomal-dominant form, but the enzyme deficiency in Refsum disease is inherited in an autosomal-recessive pattern.
Each form of porphyria is explained by a different spectrum of upstream accumulations of porphyrins and porphyrin precursors.
Etiology
The causes of refsum disease and hepatic porphyrias are as follows:
Autosomal Recessive Inheritance
Biochemical Pathogenesis
Genetic Basis
Biochemical Pathogenesis
Genetics
Prognostic Factors
The right medication and food restrictions are crucial to the prognosis of hepatic porphyrias and Refsum disease.
Infantile Refsum illness typically has a 5 to 13-year survival rate, with some cases lasting into adulthood. The fourth to fifth decade of life is when adults with Refsum sickness survive.
Monitoring porphyrin levels and using D10W and hemin infusions correctly are essential for survival during an acute porphyric attack.
Even with the right care, up to 25% of people who have acute episodes of acute intermittent porphyria die.
Clinical History
Consanguinity should be taken into consideration if the primary symptoms of cerebellar ataxia and blurred vision are present.
Heterozygotes following selected diets high in dairy and beef may experience isolated cases.
The porphyrias exhibit an autosomal-dominant pattern, and the typical family has a history of simultaneous mental and neurologic symptoms, reddish-brown, fluorescent urine, and combinations of photodermatitis and stomach crises.
Drug-induced exacerbations in hepatic porphyrias may be a problem for patients, but not for erythropoietic protoporphyrias, which have clear cutaneous photosensitivity.
Severe abdominal pain, muscle weakness, confusion, agitation, hallucinations.
Differential Diagnoses
Multiple Sclerosis
Friedreich Ataxia
Pediatric Guillain-Barre Syndrome
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
The only known treatment for Refsum illness is to limit consumption of beef and dairy products.
Any medication taken for an extended period carries the risk of increasing cytochrome P450 activity and heme group synthesis.
In the porphyrin pathway’s rate-limiting phase, delta-ALA synthase activity is accelerated by increased heme group synthesis.
This leads to an overabundance of porphyrins at stages of the heme biosynthesis pathway because of inherited poor enzyme activity.
When compared to a placebo, Givosiran caused a 74% mean decrease in the annualized composite rate of porphyria events in patients with acute intermittent porphyria.
A 90% decrease in the median annualized attack rate (AAR) was also seen, with 50% of patients receiving givosiran experiencing no attacks compared to 16.3% receiving a placebo.
ALA and porphobilinogen, the neurotoxic liver heme intermediate that trigger attacks and other symptoms of AHP illness, also showed a consistent (~90%) decrease from baseline.
Tolerance of new anticonvulsants for several months does not indicate safety because larger amounts of delta-ALA synthase may be induced gradually over time.
The most effective treatment for porphyria cutanea tarda’s photocutaneous symptoms is therapeutic phlebotomy. A period of remission lasting six to twelve months is possible if serum porphyrins are reduced to 20% of prephlebotomy levels over two to three months.
Strict avoidance of foods high in phytanic acid is the foundation of environmental therapy for people with Refsum Disease.
Environmental modification for hepatic porphyria patients is to reduce exposure to recognized triggers that might cause acute attacks.
Avoid fasting or crash diets, which can precipitate attacks. Minimize tripping hazards due to poor night vision.
Proper awareness about refsum disease and hepatic porphyrias should be provided and its related causes with management strategies.
Appointments with endocrinologist and preventing recurrence of disorder is an ongoing life-long effort.
Use of Intravenous Nutritional Therapy
Dextrose:
Using regular endogenous energy metabolism, the “glucose effect” lowers the rate of porphyrin production, reversing or stopping acute porphyric assaults.
Use of Biologicals
Hemin:
Hemin infusion is designed specifically for reversing severe acute porphyric attacks.
Use of Anticonvulsants
Gabapentin:
It relieves the pain of PHN to change the way the body senses pain.
Use of Antipsychotics
Loxapine succinate:
It blocks mesolimbic D1 and D2 receptors in the brain also consists of anti-serotonin 5HT2 activity.
Use of RNAi Agents
Givosiran:
The increased levels of liver ALAS1 mRNA are decreased by small-interfering RNA agents that use RNA interference to break down amino levulinate synthase 1 (ALAS1) mRNA in hepatocytes.
Only those individuals who have life-threatening acute episodes or whose symptoms worsen despite medication are eligible for liver transplantation.
Patients with recurrent episodes who are not responding to treatment may benefit from liver transplantation.
Acute porphyria patients are susceptible to exploratory laparoscopy for a distinct acute abdomen due to the lack of rebound soreness.
If an abdominal CT scan is inconclusive, a high preoperative urine PBG level should reduce the need for a surgical abdominal exploration.
The anesthesiologist should be ready to apply glucose loading after surgery and be aware of the possibility of aggravation from fasting or general anesthesia in patients with porphyria.
In the acute phase, the goal is to reduce phytanic acid levels that prevent the progression of neurological and systemic symptoms.
In maintenance phase, the goal is to long-term prevention of symptom progression and complications.
In supportive care and management phase, patients should receive required attention such as lifestyle modification and surgical interventional procedures.
The regular follow-up visits with the endocrinologist are scheduled to check the improvement of patients along with treatment response.
»
Home » CAD » Refsum Disease and the Hepatic Porphyrias (Diseases of Tetrapyrrole Metabolism)
Refsum Disease and the Hepatic Porphyrias (Diseases of Tetrapyrrole Metabolism)
Updated :
December 9, 2025
The aberrant metabolism of big tetrapyrrole molecules causes remissions and exacerbations in the rare inherited neurodegenerative diseases known as hepatic porphyrias and Refsum disease.
The prosthetic group of hemoglobin, heme, and the photosynthetic pigment chlorophyll and are two typical examples of big tetrapyrrole molecules.
The phytol a massive hydrocarbon alcoholic substituent on chlorophyll is a notable exception to the rule that side groups on both species involve very tiny organic groups.
Foods and medications that raise the levels of the relevant biological toxin, which might cause or prolong an exacerbation, must be avoided by patients in both disease groups.
The iron-containing tetrapyrrole heme is necessary for a various of biological processes including oxidative metabolism, gas transport, and xenobiotic detoxification.
A collection of metabolic diseases known as porphyrias are caused by defects in one of the eight enzymes in the heme biosynthesis pathway, which leads to the buildup of organic substances known as porphyrins.
Even though refsum sickness is uncommon, heterozygote carriers who consume a lot of beef and dairy products may be at risk.
Approximately 1 in 100,000 people are thought to have acute intermittent porphyria (AIP), the most prevalent form of acute hepatic porphyria (AHP).
Neurologic dysfunction is characterized by remissions and exacerbations in both Refsum disease and hepatic porphyrias. These might resolve entirely or show progressive deterioration.
Porphyrias and Refsum sickness are more common in those with Caucasian ancestry. The exception is Porphyria cutanea tarda, which is observed among Black people with Bantu ancestry.
Acute intermittent porphyria in females and porphyria cutanea tarda in males may have more symptomatic attacks, although autosomal inheritance should ensure similar prevalence in both sexes.
Phytanic acid, the neurotoxic in Refsum disease, is accumulated in the brain and visceral parenchyma of those who have it due to a lack of phytanic acid alpha-hydroxylase.
Either direct absorption of phytol from ruminant fat in meat or milk or conversion of ingested phytol are the sources of phytanic acid.
The enzyme deficiencies associated with hepatic porphyrias are usually inherited in an autosomal-dominant form, but the enzyme deficiency in Refsum disease is inherited in an autosomal-recessive pattern.
Each form of porphyria is explained by a different spectrum of upstream accumulations of porphyrins and porphyrin precursors.
The causes of refsum disease and hepatic porphyrias are as follows:
Autosomal Recessive Inheritance
Biochemical Pathogenesis
Genetic Basis
Biochemical Pathogenesis
The right medication and food restrictions are crucial to the prognosis of hepatic porphyrias and Refsum disease.
Infantile Refsum illness typically has a 5 to 13-year survival rate, with some cases lasting into adulthood. The fourth to fifth decade of life is when adults with Refsum sickness survive.
Monitoring porphyrin levels and using D10W and hemin infusions correctly are essential for survival during an acute porphyric attack.
Even with the right care, up to 25% of people who have acute episodes of acute intermittent porphyria die.
Consanguinity should be taken into consideration if the primary symptoms of cerebellar ataxia and blurred vision are present.
Heterozygotes following selected diets high in dairy and beef may experience isolated cases.
The porphyrias exhibit an autosomal-dominant pattern, and the typical family has a history of simultaneous mental and neurologic symptoms, reddish-brown, fluorescent urine, and combinations of photodermatitis and stomach crises.
Drug-induced exacerbations in hepatic porphyrias may be a problem for patients, but not for erythropoietic protoporphyrias, which have clear cutaneous photosensitivity.
Severe abdominal pain, muscle weakness, confusion, agitation, hallucinations.
Multiple Sclerosis
Friedreich Ataxia
Pediatric Guillain-Barre Syndrome
The only known treatment for Refsum illness is to limit consumption of beef and dairy products.
Any medication taken for an extended period carries the risk of increasing cytochrome P450 activity and heme group synthesis.
In the porphyrin pathway’s rate-limiting phase, delta-ALA synthase activity is accelerated by increased heme group synthesis.
This leads to an overabundance of porphyrins at stages of the heme biosynthesis pathway because of inherited poor enzyme activity.
When compared to a placebo, Givosiran caused a 74% mean decrease in the annualized composite rate of porphyria events in patients with acute intermittent porphyria.
A 90% decrease in the median annualized attack rate (AAR) was also seen, with 50% of patients receiving givosiran experiencing no attacks compared to 16.3% receiving a placebo.
ALA and porphobilinogen, the neurotoxic liver heme intermediate that trigger attacks and other symptoms of AHP illness, also showed a consistent (~90%) decrease from baseline.
Tolerance of new anticonvulsants for several months does not indicate safety because larger amounts of delta-ALA synthase may be induced gradually over time.
The most effective treatment for porphyria cutanea tarda’s photocutaneous symptoms is therapeutic phlebotomy. A period of remission lasting six to twelve months is possible if serum porphyrins are reduced to 20% of prephlebotomy levels over two to three months.
Endocrinology, Metabolism
Strict avoidance of foods high in phytanic acid is the foundation of environmental therapy for people with Refsum Disease.
Environmental modification for hepatic porphyria patients is to reduce exposure to recognized triggers that might cause acute attacks.
Avoid fasting or crash diets, which can precipitate attacks. Minimize tripping hazards due to poor night vision.
Proper awareness about refsum disease and hepatic porphyrias should be provided and its related causes with management strategies.
Appointments with endocrinologist and preventing recurrence of disorder is an ongoing life-long effort.
Dextrose:
Using regular endogenous energy metabolism, the “glucose effect” lowers the rate of porphyrin production, reversing or stopping acute porphyric assaults.
Endocrinology, Metabolism
Hemin:
Hemin infusion is designed specifically for reversing severe acute porphyric attacks.
Endocrinology, Reproductive/Infertility
Gabapentin:
It relieves the pain of PHN to change the way the body senses pain.
Endocrinology, Reproductive/Infertility
Loxapine succinate:
It blocks mesolimbic D1 and D2 receptors in the brain also consists of anti-serotonin 5HT2 activity.
Endocrinology, Reproductive/Infertility
Givosiran:
The increased levels of liver ALAS1 mRNA are decreased by small-interfering RNA agents that use RNA interference to break down amino levulinate synthase 1 (ALAS1) mRNA in hepatocytes.
Endocrinology, Reproductive/Infertility
Only those individuals who have life-threatening acute episodes or whose symptoms worsen despite medication are eligible for liver transplantation.
Patients with recurrent episodes who are not responding to treatment may benefit from liver transplantation.
Acute porphyria patients are susceptible to exploratory laparoscopy for a distinct acute abdomen due to the lack of rebound soreness.
If an abdominal CT scan is inconclusive, a high preoperative urine PBG level should reduce the need for a surgical abdominal exploration.
The anesthesiologist should be ready to apply glucose loading after surgery and be aware of the possibility of aggravation from fasting or general anesthesia in patients with porphyria.
Endocrinology, Reproductive/Infertility
In the acute phase, the goal is to reduce phytanic acid levels that prevent the progression of neurological and systemic symptoms.
In maintenance phase, the goal is to long-term prevention of symptom progression and complications.
In supportive care and management phase, patients should receive required attention such as lifestyle modification and surgical interventional procedures.
The regular follow-up visits with the endocrinologist are scheduled to check the improvement of patients along with treatment response.
Refsum Disease and the Hepatic Porphyrias (Diseases of Tetrapyrrole Metabolism)
Updated :
December 9, 2025
The aberrant metabolism of big tetrapyrrole molecules causes remissions and exacerbations in the rare inherited neurodegenerative diseases known as hepatic porphyrias and Refsum disease.
The prosthetic group of hemoglobin, heme, and the photosynthetic pigment chlorophyll and are two typical examples of big tetrapyrrole molecules.
The phytol a massive hydrocarbon alcoholic substituent on chlorophyll is a notable exception to the rule that side groups on both species involve very tiny organic groups.
Foods and medications that raise the levels of the relevant biological toxin, which might cause or prolong an exacerbation, must be avoided by patients in both disease groups.
The iron-containing tetrapyrrole heme is necessary for a various of biological processes including oxidative metabolism, gas transport, and xenobiotic detoxification.
A collection of metabolic diseases known as porphyrias are caused by defects in one of the eight enzymes in the heme biosynthesis pathway, which leads to the buildup of organic substances known as porphyrins.
Even though refsum sickness is uncommon, heterozygote carriers who consume a lot of beef and dairy products may be at risk.
Approximately 1 in 100,000 people are thought to have acute intermittent porphyria (AIP), the most prevalent form of acute hepatic porphyria (AHP).
Neurologic dysfunction is characterized by remissions and exacerbations in both Refsum disease and hepatic porphyrias. These might resolve entirely or show progressive deterioration.
Porphyrias and Refsum sickness are more common in those with Caucasian ancestry. The exception is Porphyria cutanea tarda, which is observed among Black people with Bantu ancestry.
Acute intermittent porphyria in females and porphyria cutanea tarda in males may have more symptomatic attacks, although autosomal inheritance should ensure similar prevalence in both sexes.
Phytanic acid, the neurotoxic in Refsum disease, is accumulated in the brain and visceral parenchyma of those who have it due to a lack of phytanic acid alpha-hydroxylase.
Either direct absorption of phytol from ruminant fat in meat or milk or conversion of ingested phytol are the sources of phytanic acid.
The enzyme deficiencies associated with hepatic porphyrias are usually inherited in an autosomal-dominant form, but the enzyme deficiency in Refsum disease is inherited in an autosomal-recessive pattern.
Each form of porphyria is explained by a different spectrum of upstream accumulations of porphyrins and porphyrin precursors.
The causes of refsum disease and hepatic porphyrias are as follows:
Autosomal Recessive Inheritance
Biochemical Pathogenesis
Genetic Basis
Biochemical Pathogenesis
The right medication and food restrictions are crucial to the prognosis of hepatic porphyrias and Refsum disease.
Infantile Refsum illness typically has a 5 to 13-year survival rate, with some cases lasting into adulthood. The fourth to fifth decade of life is when adults with Refsum sickness survive.
Monitoring porphyrin levels and using D10W and hemin infusions correctly are essential for survival during an acute porphyric attack.
Even with the right care, up to 25% of people who have acute episodes of acute intermittent porphyria die.
Consanguinity should be taken into consideration if the primary symptoms of cerebellar ataxia and blurred vision are present.
Heterozygotes following selected diets high in dairy and beef may experience isolated cases.
The porphyrias exhibit an autosomal-dominant pattern, and the typical family has a history of simultaneous mental and neurologic symptoms, reddish-brown, fluorescent urine, and combinations of photodermatitis and stomach crises.
Drug-induced exacerbations in hepatic porphyrias may be a problem for patients, but not for erythropoietic protoporphyrias, which have clear cutaneous photosensitivity.
Severe abdominal pain, muscle weakness, confusion, agitation, hallucinations.
Multiple Sclerosis
Friedreich Ataxia
Pediatric Guillain-Barre Syndrome
The only known treatment for Refsum illness is to limit consumption of beef and dairy products.
Any medication taken for an extended period carries the risk of increasing cytochrome P450 activity and heme group synthesis.
In the porphyrin pathway’s rate-limiting phase, delta-ALA synthase activity is accelerated by increased heme group synthesis.
This leads to an overabundance of porphyrins at stages of the heme biosynthesis pathway because of inherited poor enzyme activity.
When compared to a placebo, Givosiran caused a 74% mean decrease in the annualized composite rate of porphyria events in patients with acute intermittent porphyria.
A 90% decrease in the median annualized attack rate (AAR) was also seen, with 50% of patients receiving givosiran experiencing no attacks compared to 16.3% receiving a placebo.
ALA and porphobilinogen, the neurotoxic liver heme intermediate that trigger attacks and other symptoms of AHP illness, also showed a consistent (~90%) decrease from baseline.
Tolerance of new anticonvulsants for several months does not indicate safety because larger amounts of delta-ALA synthase may be induced gradually over time.
The most effective treatment for porphyria cutanea tarda’s photocutaneous symptoms is therapeutic phlebotomy. A period of remission lasting six to twelve months is possible if serum porphyrins are reduced to 20% of prephlebotomy levels over two to three months.
Endocrinology, Metabolism
Strict avoidance of foods high in phytanic acid is the foundation of environmental therapy for people with Refsum Disease.
Environmental modification for hepatic porphyria patients is to reduce exposure to recognized triggers that might cause acute attacks.
Avoid fasting or crash diets, which can precipitate attacks. Minimize tripping hazards due to poor night vision.
Proper awareness about refsum disease and hepatic porphyrias should be provided and its related causes with management strategies.
Appointments with endocrinologist and preventing recurrence of disorder is an ongoing life-long effort.
Dextrose:
Using regular endogenous energy metabolism, the “glucose effect” lowers the rate of porphyrin production, reversing or stopping acute porphyric assaults.
Endocrinology, Metabolism
Hemin:
Hemin infusion is designed specifically for reversing severe acute porphyric attacks.
Endocrinology, Reproductive/Infertility
Gabapentin:
It relieves the pain of PHN to change the way the body senses pain.
Endocrinology, Reproductive/Infertility
Loxapine succinate:
It blocks mesolimbic D1 and D2 receptors in the brain also consists of anti-serotonin 5HT2 activity.
Endocrinology, Reproductive/Infertility
Givosiran:
The increased levels of liver ALAS1 mRNA are decreased by small-interfering RNA agents that use RNA interference to break down amino levulinate synthase 1 (ALAS1) mRNA in hepatocytes.
Endocrinology, Reproductive/Infertility
Only those individuals who have life-threatening acute episodes or whose symptoms worsen despite medication are eligible for liver transplantation.
Patients with recurrent episodes who are not responding to treatment may benefit from liver transplantation.
Acute porphyria patients are susceptible to exploratory laparoscopy for a distinct acute abdomen due to the lack of rebound soreness.
If an abdominal CT scan is inconclusive, a high preoperative urine PBG level should reduce the need for a surgical abdominal exploration.
The anesthesiologist should be ready to apply glucose loading after surgery and be aware of the possibility of aggravation from fasting or general anesthesia in patients with porphyria.
Endocrinology, Reproductive/Infertility
In the acute phase, the goal is to reduce phytanic acid levels that prevent the progression of neurological and systemic symptoms.
In maintenance phase, the goal is to long-term prevention of symptom progression and complications.
In supportive care and management phase, patients should receive required attention such as lifestyle modification and surgical interventional procedures.
The regular follow-up visits with the endocrinologist are scheduled to check the improvement of patients along with treatment response.
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