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Hereditary Coproporphyria

Cpo Coproporphyrinogn Oxid Def

Hereditary coproporphyria (HC) is a rare disease originating from detrimental changes in the gene of the mitochondrial enzyme coproporphyrin-III oxidase (CPO). The enzyme malfunction results in pathologically high urine concentrations of porphobilinogen and 5-aminolevulinic acid. There is no cure for hereditary coproporphyria but a carbohydrate-rich diet, as well as general drug and alcohol abstinence, reduce the risk of acute porphyria attacks.


Presentation

Hereditary coproporphyria is passed on in an autosomal dominant manner. It is caused by a set of mutations of the CPOX gene which drastically downregulates the enzymatic activity of CPO. CPO is involved in porphyrin and heme biosynthesis [1] [2].

Hereditary coproporphyria can develop in an acute and a chronic form. In its acute manifestation, patients may suffer from persisting nausea, vomiting attacks, severe epigastric abdominal and back pain lasting for several days, constipation, obstipation, cortical blindness, hypertension, hyponatremia, tachycardia, reddish urine and discrete seizure episodes, which can also lead to depression. Psychological symptoms typically present concomitantly with abdominal symptoms. Patients can also exhibit motor neuropathies characteristic of Guillain-Barré syndrome. Diffuse pain in the upper body has also been reported. Hereditary coproporphyria is usually asymptomatic between acute attacks.

In its chronic form, hereditary coproporphyria patients typically develop a long-lasting cutaneous photosensitivity in sun-exposed body parts such as hands and face. These body parts typically show a very fragile skin, hyperpigmented scars and bullae [3].

The probability of prevalence of the pathogenic CPOX mutations is equal in both, men and women. However, acute attacks affect women more often, in particular between menarche and menopause (age- 16 to 45). Attacks before puberty are very rare [3].

Abdominal Pain
  • A case of hereditary coproporphyria was reported, he was a 21-year-old farmer, presenting with abdominal pain and fever.[ncbi.nlm.nih.gov]
  • A 23-year-old man with epilepsy and a past history of abdominal pain and ileus, developed hypertension and arm and bulbar weakness when valproic acid and carbamazepine were reinitiated.[ncbi.nlm.nih.gov]
  • In the immediate post-transplant periods she displayed abdominal pain and transient uroporphyrin elevation in parallel with slightly elevated (15 ng/mL) tacrolimus concentrations.[ncbi.nlm.nih.gov]
  • Other symptoms included intermittent headache, fatigue, abdominal pain and nausea. Porphyrin studies were markedly raised, with features consistent with hereditary coproporphyria (HCP).[ncbi.nlm.nih.gov]
  • Both are considered rare differential diagnosis for acute abdominal pain. Case report 17 year old boy of Algerian origin presented with long history of recurrent episodes of fever, abdominal pain since infancy.[ped-rheum.biomedcentral.com]
Nausea
  • Hereditary coproporphyria (HCP) is a rare inherited form of liver (hepatic) porphyria, characterized by neurological symptoms in the form of episodes (acute attacks) of stomach pain, nausea, vomiting, weakness, numbness, and pain in the hands and feet[rarediseases.info.nih.gov]
  • Other symptoms included intermittent headache, fatigue, abdominal pain and nausea. Porphyrin studies were markedly raised, with features consistent with hereditary coproporphyria (HCP).[ncbi.nlm.nih.gov]
  • In its acute manifestation, patients may suffer from persisting nausea, vomiting attacks, severe epigastric abdominal and back pain lasting for several days, constipation, obstipation, cortical blindness, hypertension, hyponatremia, tachycardia, reddish[symptoma.com]
Hyperkeratosis
  • Microscopic examination from a cutaneous biopsy showed no specific lesions, only hyperplasic epidermis, hypergranulosis, hyperkeratosis with irregular acanthosis, hypoderm and derm inflammation with predominant polynuclear cells.[doi.org]
Osteopenia
  • However, borderline osteopenia secondary to hypoestrogenism has been noted. Although these analogues are potent in suppressing estrogen-induced porphyric symptoms, due precautions should be taken to avoid bone demineralization in the long-term use.[ncbi.nlm.nih.gov]
Suicidal Ideation
  • Ms F's mood gradually became euthymic, suicidal ideations and anxiety disappeared. At 5-month follow-up, while still on lamotrigine, her porphyria was asymptomatic.[ncbi.nlm.nih.gov]
Seizure
  • Seizures are common in acute exacerbations of hepatic porphyria, even though the etiology is not identified in most cases. We have reported a case of normeperidine-induced seizures in a patient with hereditary coproporphyria.[ncbi.nlm.nih.gov]
  • Proper drug selection is most difficult when it comes to treatment of the seizures that can accompany HCP, as most anti-seizure medications can make the symptoms worse.[en.wikipedia.org]
  • A 9-year-old boy with mental deterioration and epilepsy suffered an acute attack of hereditary coproporphyria associated with worsening of seizure control.[ncbi.nlm.nih.gov]
  • Signs and symptoms present during the attacks may include body pain, nausea and vomiting, increased heart rate ( tachycardia ), and high blood pressure. [2] Less common symptoms include seizures, skin lesions, and paralysis of the arms and legs, body[rarediseases.info.nih.gov]
Personality Change
  • Other symptoms include: Muscle pain Muscle weakness or paralysis Numbness or tingling Pain in the arms or legs Pain in the back Personality changes Attacks can sometimes be life-threatening, producing: Low blood pressure Severe electrolyte imbalances[medlineplus.gov]
  • Symptoms are pain in gut, limbs, or torso; paralysis, vomiting, constipation, personality changes, paranoia. These symptoms can last for hours, days, or weeks.[myporphyria.com]
Mental Deterioration
  • A 9-year-old boy with mental deterioration and epilepsy suffered an acute attack of hereditary coproporphyria associated with worsening of seizure control.[ncbi.nlm.nih.gov]
Red Urine
  • His manifestations were composed of all classical symptoms of acute hepatic porphyrias i.e. convulsions, psychosis, hypertension and respiratory failure as well as dark red urine with positive Watson-Schwartz test.[ncbi.nlm.nih.gov]
  • He subsequently developed dark red urine, with dipstick testing showing ketones only. He additionally described transient auditory and visual hallucinations. Urine porphobilinogen was increased, consistent with an acute attack of porphyria.[journals.lww.com]
  • urine layers -- Clear chloroform & clear butanol layers Neurological/Psychiatric Forms of Porphyria -Abdominal Pain -Chest Pain -Nausea -Confusion -Depression -Hallucinations -Psychosis Acute Intermittent Porphyria -Enzyme defect: Hydrozymethylbilane[quizlet.com]
  • Patients usually have blistering skin lesions, hypertrichosis, scarring, and red urine during infancy or childhood. Concurrent conditions that affect the liver may worsen the disease severity; this has been described in a toddler with hepatitis A.[clinicaladvisor.com]
  • This treatment is not effective in other por- phyrias [19]. 36.8 Hepatoerythropoietic Porphyria 36.8.1 Clinical Presentation This rare disease is clinically similar to congenital erythro- poietic porphyria and usually presents with red urine and blistering[123doc.org]

Workup

In the initial screening procedure, it is reasonable to probe 5-aminolevulinic acid and porphobilinogen urine levels, which are expected to be increased by at least a factor of three during attacks. Urine porphyrin concentrations are another viable cross-check. Importantly, urine porphyrin levels can reduce back to normal or remain mildly elevated between attacks [4] [5]. Slightly increased but constant urine coproporphyrin levels are nonspecific and thus insufficient to corroborate the diagnosis. Serum sodium concentration should be checked in patients during attacks, since hyponatremia a quite common symptom. It is hardly feasible and advisable to directly measure the enzymatic activity of CPO.

Hereditary coproporphyria diagnosis mainly relies on solid evidence of elevated concentrations of coproporphyrins in the feces after a positive initial screening. Fecal coproporphyrin III levels can be up to 200 times higher than normal in absolute terms [6]. A direct initial test of fecal coproporphyrin III levels without further backup tests lacks specificity and sensitivity. The ratio of fecal coproporphyrin III to coproporphyrin concentrations has been shown to be a suitable check to probe for hereditary coproporphyria in adults. A dominant contribution (60-95%) of the coproporphyrin III isomer in this ratio is characteristic of hereditary coproporphyria, while it is smaller than 50% in control groups [7] [8].

Abdominal pain symptoms in hereditary porphyria have been rationalized with elevated urine levels of the heme precursor molecule delta-aminolevulinic acid. Administration of hemin relieves pain symptoms during attacks because it inhibits the catalysis of delta-aminolevulinic acid by aminolevulinic acid synthase-1 [9].

Treatment

  • We report a successful treatment with lamotrigine of a patient with hereditary coproporphyria presenting with affective and psychotic symptoms.[ncbi.nlm.nih.gov]
  • Although haem arginate infusion is known as a treatment for severe acute attacks of HCP, the effectiveness of regular infusions as maintenance therapy has not been established.[ncbi.nlm.nih.gov]
  • Treatment is based on preventing the symptoms. An acute attack requires hospitalization, medications, and treatment with heme therapy. [4] Last updated: 9/4/2019[rarediseases.info.nih.gov]
  • Proper drug selection is most difficult when it comes to treatment of the seizures that can accompany HCP, as most anti-seizure medications can make the symptoms worse.[en.wikipedia.org]

Prognosis

  • Prognosis With early diagnosis and management, attacks from porphyria are rarely fatal. Acute attacks are more rare than in cases of acute intermittent porphryia and, if the triggering factors are eliminated, the disease is rarely progressive.[orpha.net]
  • The prognosis is usually good if the disease is recognized and treated promptly, before nerve damage develops.[porphyriafoundation.blogspot.com]
  • Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore). 1992 Jan. 71(1):1-13. [Medline]. Laiwah AC, McColl KE. Management of attacks of acute porphyria.[emedicine.medscape.com]

Etiology

  • Results of exhaustive investigation of etiological factors for hepatocellular carcinoma were negative. Results of microscopic histological analysis of the nontumorous liver were normal.[ncbi.nlm.nih.gov]
  • Seizures are common in acute exacerbations of hepatic porphyria, even though the etiology is not identified in most cases. We have reported a case of normeperidine-induced seizures in a patient with hereditary coproporphyria.[ncbi.nlm.nih.gov]
  • After an extensive workup, the etiology of the liver failure was determined to be due to hereditary coprophorphyria (HCP).[ncbi.nlm.nih.gov]
  • Etiology Hereditary coproporphyria is caused by a deficiency of coproporphyrinogen oxidase (CPO, the sixth enzyme in the heme biosynthesis pathway) that leads to an accumulation of porphyrins and their precursors in the liver (delta-aminolevulinic acid[orpha.net]

Epidemiology

  • Summary Epidemiology The prevalence in Europe is estimated at about 1/1,000,000. Clinical description The disease manifests after puberty and preferentially affects women.[orpha.net]
  • Our findings add substantially to knowledge of the molecular epidemiology of HCP, show that single copies of CPO mutations that are known or predicted to cause "homozygous" HCP or harderoporphyria can produce typical HCP in adults, and demonstrate that[ncbi.nlm.nih.gov]
  • […] neurovisceral attacks always have elevations of porphobilinogen and ALA, researchers still are unclear about how this leads to the symptomatic disease because most patients with the genetic defect have excessive porphyrin secretion but no symptoms. [1] Epidemiology[emedicine.medscape.com]
Sex distribution
Age distribution

Pathophysiology

  • In an oral stomatology practice, a group of patients having oral conditions with unknown pathophysiology and multiple systemic complaints were evaluated for porphyrin abnormalities. Blood enzymes, urine and stool porphyrin panels were usually run.[ncbi.nlm.nih.gov]
  • The pathophysiology of both neurologic and psychiatric symptoms is not fully understood.[ncbi.nlm.nih.gov]
  • Pathophysiology Coproporphyria is an autosomal dominant disease that results from defects in the enzyme coproporphyrinogen oxidase. This enzyme speeds the conversion of coproporphyrinogen to protoporphyrinogen.[emedicine.medscape.com]

Prevention

  • Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance. In selected cases, frequent noncyclic attacks can be prevented by once- or twice-weekly infusions of hemin.[porphyriafoundation.blogspot.com]
  • Treatment is based on preventing the symptoms. An acute attack requires hospitalization, medications, and treatment with heme therapy. [4] Last updated: 9/4/2019[rarediseases.info.nih.gov]
  • The identification of the genetic defect in HCP families is of crucial importance to detect the carrier status which allows counselling to prevent possible triggering factors, e.g. certain drugs, alcohol, or fasting.[ncbi.nlm.nih.gov]
  • Avoiding your triggers will help prevent bouts of symptoms. Remember that everyone with porphyria is different. Some people have milder symptoms than others. Treatments can help you feel better and prevent complications.[webmd.com]

References

Article

  1. Dong-Sun L, Flachsová E, Bodnárová M, Demeler B, Martásek P, Raman CS. Structural basis of hereditary coproporphyria. Proc Natl Acad Sci U S A. 2005;102(40):14232–14237.
  2. Rosipal R, Lamoril J, Puy H, et al. Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update. Hum Mutat. 1999;13(1):44-53.
  3. Bissell DM, Wang B, Lai J. Hereditary Coproporphyria. In: Pagon RA, Adam MP, Ardinger HH, et al. eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK114807/ Accessed March 27th 2017.
  4. Roshal M, Turgeon J, Rainey PM. Rapid quantitative method using spin columns to measure porphobilinogen in urine. Clin Chem. 2008;54(2):429-431.
  5. Stein P, Badminton M, Barth J, Rees D, Stewart MF. Best practice guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50(3):217-223.
  6. Whatley SD, Mason NG, Woolf JR, Newcombe RG, Elder GH, Badminton MN. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene. Clin Chem. 2009;55(7):1406-1414.
  7. Kühnel A, Gross U, Doss MO. Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients. Clin Biochem. 2000;33(6):465-473.
  8. Blake D, McManus J, Cronin V, Ratnaike S. Fecal coproporphyrin isomers in hereditary coproporphyria. Clin Chem. 1992;38(1):96-100.
  9. Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med. 2015;128:313–317.

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Last updated: 2019-07-11 20:32