Chromoprotein metabolism disorders: diagnosis and treatment

Chromoproteins are proteins with colored prosthetic groups (heme, flavins, etc.), which determine their functions in respiration, detoxification, oxygen transport, and skin photobiology. Disorders of chromoprotein metabolism manifest as either an excess or deficiency of normal pigments (e.g., bilirubin, melanin), or the accumulation of abnormal derivatives (porphyrins, lipofuscin), or the formation of dysfunctional forms of hemoglobin (methemoglobin, sulfhemoglobin). Clinically, this spectrum ranges from benign cosmetic conditions to life-threatening crises and liver failure.

The modern practical framework distinguishes three large groups: 1) hemoglobinogenic disorders (jaundice, hemosiderosis/hemochromatosis, dyshemoglobinemia), 2) proteinogenic/melanin disorders (hyper- and hypomelanosis, vitiligo, albinism), 3) lipidogenic (lipofuscinoses, including neuronal ceroid lipofuscinoses). A separate block is the porphyrias - hereditary/acquired defects of heme biosynthesis, now classified as acute hepatic porphyrias (AHP) and cutaneous forms. [1]

The significance of this topic lies in the high prevalence of some subtypes (for example, Gilbert's syndrome, which can affect up to 2-13% of the population) compared to the extreme rarity and underdiagnosis of others (porphyrias, neuronal lipofuscinoses). This requires a clear diagnostic algorithm to quickly distinguish a harmless condition from one that threatens organ failure. [2]

In recent years, effective targeted therapies have emerged: givosiran (an ALAS1 inhibitor) for the prevention of AHP attacks, afamelanotide (an MC1R agonist) for erythropoietic protoporphyria (EPP), and the indications for cerliponase alfa (enzyme replacement therapy for CLN2 disease) have been expanded - all of which are changing the prognosis for patients. [3]

Code according to ICD-10 and ICD-11

The codes depend on the mechanism and the underlying syndrome. In everyday practice, the most commonly used ICD-10 sections are E80 (disorders of porphyrin and bilirubin metabolism), E83.11 (hemochromatosis), D74 (methemoglobinemia), and L80-L81 (disorders of skin pigmentation). In ICD-11, block 5C58 covers porphyrias and heme synthesis errors, 5C64.10 covers iron overload; dermatological pigment disorders are grouped in ED60-ED64 (including vitiligo ED63.0, melasma ED60.1). [4]

Below is a convenient summary table for the clinician (ICD-10 on the left, ICD-11 on the right for the corresponding conditions).

Table 1. ICD codes for key disorders of chromoprotein metabolism

State	ICD-10	ICD-11
Porphyria (general section)	E80.0-E80.2	5C58.1 (subcodes by type, e.g. 5C58.10 PCT)
Porphyria cutanea tarda (PCT)	E80.1	5C58.10
Acute hepatic porphyrias (AHP)*	E80.2 (other/unspecified) + clarifying	5C58.1x (AIP/HCP/VP/ALAD-porf.)
Bilirubin disorders (Gilbert, Crigler-Najjar)	E80.4-E80.6	5C5Y.0 (other disorders of bilirubin metabolism)**
Hemochromatosis	E83.11 (including E83.110 hereditary)	5C64.10 (iron overload diseases)
Methemoglobinemia	D74.x	3A74.0 Methemoglobinemia
Vitiligo	L80	ED63.0
Melasma	L81.4 (other melanin hyperpigmentation)	ED60.1
* AIP/HCP/VP/ALAD in ICD-11 are divided into subcodes of group 5C58.
** In ICD-11, bilirubin details are available in sections 5C5 (depending on the version/localization). See sources for codes above. [5]

Epidemiology

Porphyrias are rare diseases: the combined prevalence of acute liver porphyrias is about 5 per 100,000; PCT is the most common porphyria (approximately 10 per 100,000, varying by country from 1:5,000 to 1:70,000); EPP is approximately 1:50,000-1:100,000, but some biobank estimates indicate underdiagnosis. [6]

Gilbert's syndrome is the most common cause of moderate unconjugated hyperbilirubinemia: 2-13% of the population with variations by ethnicity and region. [7]

Hemochromatosis (HFE-related) is one of the most common hereditary diseases in Europeans; the prevalence of the C282Y homozygote genotype is ≈ 0.3-0.6% in Northern Europe, but the clinical manifestation is lower due to incomplete penetrance (for codes see ICD section). [8]

Ceroid lipofuscinosis neuronalis type 2 (CLN2) is an ultra-rare disease (<1 in 1,000,000), but enzyme replacement therapy with cerliponase alfa has been available since 2017, with indications expanded to all children, including those under 3 years of age, in 2024. [9]

Table 2. Prevalence estimates

Nosology	Approximate prevalence
Acute hepatic porphyrias (AHP, in total)	≈ 5 per 100,000
PCT	10 per 100,000 (varies from 1:5,000 to 1:70,000)
EPP	1:50,000-1:100,000 (in some estimates it is higher)
Gilbert's syndrome	2-13% of the population
CLN2 (NCL-2)	< 1 in 1,000,000

Reasons

Hemoglobinogenic disorders include: 1) heme/bilirubin catabolism disorders (UGT1A1 defects in Gilbert/Crigler-Najjar; cholestasis/obstruction), 2) iron overload (HFE mutations, multiple transfusions), 3) dyshemoglobinemia (methemoglobinemia due to oxidants or congenital enzyme defects). [10]

Porphyrias are caused by a deficiency of heme-synthesizing enzymes. Acute hepatic porphyrias (AIP, HCP, VP, ALAD deficiency) cause neurovisceral crises; cutaneous forms (PCT, EPP, CEP) present with photosensitivity and blisters/erosions. Triggers include drugs that induce cytochrome P450, hormones, fasting, infections, and alcohol. [11]

Proteinogenic disorders are associated with changes in melanogenesis (melasma, post-inflammatory hyperpigmentation) or loss of melanocytes (vitiligo). Lipidogenic disorders are associated with the accumulation of lipofuscin (aging, cachexia) or ceroid (NCL). [12]

Table 3. Pathogenetic "targets"

Group	Key defect	Examples
Bilirubin	Conjugation/excretion	Gilbert, Crigler-Nayyar, cholestasis
Heme/porphyrins	Heme pathway enzymes	AIP, HCP, VP, PCT, EPP
Iron	Absorption/deposition regulation	Hereditary hemochromatosis, post-transfusion
Hemoglobin	Oxidation Fe²⁺→Fe³⁺	Methemoglobinemia, sulfhemoglobinemia
Melanin	Synthesis/cellular loss	Melasma, vitiligo
Lipofuscin	Lysosomal catabolism	CLN2, senile lipofuscinosis

Risk factors

• For PCT: alcohol, viral hepatitis, iron load, estrogens, some medications, chronic renal failure. [13]
• For AHP: female gender 15-50 years old, CYP inducers (barbiturates, some anticonvulsants, hormonal contraceptives), infections, fasting. [14]
• For methemoglobinemia: nitrates/nitrites, dapsone, benzocaine/lidocaine, some antibiotics; vulnerability in G6PD deficiency and in infants. [15]
• For hyperbilirubinemia: UGT1A1 deficiency (Gilbert), hemolysis, cholestasis, bile duct stones/tumors. [16]

Table 4. Risk factors by subgroups

Subgroup	Triggers/factors
PCT	Alcohol, HCV/HBV, iron, estrogens, nephropathy
AHP	CYP inducers, hormones, infections, fasting
Methemoglobinemia	Nitrates, dapsone, benzocaine; infants, G6PD deficiency
Hyperbilirubinemia	UGT1A1 variants, hemolysis, obstruction
Melanoses	UV radiation, pregnancy/hormones (melasma), skin inflammation
Hemochromatosis	HFE mutations, multiple transfusions

Pathogenesis

In AHP, enzyme deficiency (HMBS/CPOX/PPOX/ALAD) leads to the accumulation of porphobilinogen and δ-aminolevulinic acid, which are neurotoxic to the visceral and somatic nervous systems. Induction of ALAS1 enhances biosynthesis and triggers seizures. Therapeutic strategies aim to reduce ALAS1 and its substrates. [17]

In PCT, a defect in uroporphyrinogen decarboxylase, coupled with liver toxicity, causes accumulation of uroporphyrins, leading to skin phototoxicity and increased capillary fragility. Correction of iron/triggers normalizes biochemistry. [18]

In methemoglobinemia, the oxidation of iron in heme to Fe³⁺ blocks oxygen transport and shifts dissociation, forming a "saturation gap" between pulse oximerism and cooxymerism. Reduction is possible enzymatically (NADH/NADPH-dependent pathways) or medicinally (methylene blue, ascorbate). [19]

In Gilbert's disease, decreased UGT1A1 activity impairs bilirubin conjugation, causing fluctuating unconjugated hyperbilirubinemia without cytolysis/cholestasis.[20]

Symptoms

• Bilirubin/jaundice: icterus of the sclera/skin, dark urine (conjugated), acholic stool (obstruction), itching with cholestasis; with unconjugated hyperbilirubinemia (Gilbert) - often asymptomatic, provoked by stress/starvation. [21]
• Porphyrias: AHP - acute abdominal pain, tachycardia, hyponatremia, weakness, paresis; PCT - fragile skin, blisters on the hands, hypertrichosis; EPP - burning photopain/erythema without blisters. [22]
• Methemoglobinemia: cyanosis, “chocolate” blood, saturation gap (SpO₂ ~85% with normal PaO₂), shortness of breath, headache; in G6PD deficiency, hemolysis is possible with treatment with methylene blue. [23]
• Hemochromatosis: weakness, hyperpigmentation (“bronze skin”), arthralgia, hypogonadism, cardiomyopathy, cirrhosis. [24]

Table 5. Clinical clues "by eye"

Syndrome	Clue
Unconjugated hyperbilirubinemia	Yellow sclera without itching, normal ALT/ALP, stress provocation
AHP	Young woman, severe abdominal pain, tachycardia, hypoNa, normal CT
PCT	Blisters/erosions on the back of the hands, hypertrichosis, dark urine in the light
EPP	Burning pain from the sun without blisters in a child
Methemoglobinemia	Cyanosis + SpO₂ ~85% with normal PaO₂, chocolate blood
Hemochromatosis	Bronze skin + liver + diabetes

Classification, forms and stages

• Porphyrias: acute liver (AIP, HCP, VP, ALAD deficiency) vs. cutaneous (PCT, EPP, congenital erythropoietic, etc.). For practice, this is more important than the old schemes. [25]
• Hyperbilirubinemia: unconjugated (Gilbert, hemolysis) vs. conjugated (cholestasis/obstruction, hepatocellular cytolysis). [26]
• Dyshemoglobinemia: congenital and acquired; methemoglobinemia vs. sulfhemoglobinemia. [27]
• Iron overload: hereditary (HFE, others) and secondary (transfusions, parenteral iron). [28]

Complications and consequences

Uncontrolled AHP attacks are fraught with neuropathy, respiratory failure, chronic pain; in the long term - an increased risk of hepatocellular carcinoma. EPP can cause protoporphyrin hepatopathy with cholestatic liver failure. [29]
Long-term conjugated hyperbilirubinemia and cholestasis lead to itching, osteodeficiency, biliary cirrhosis. Iron overload affects the liver, heart, pancreas. Methemoglobinemia in severe cases leads to tissue hypoxia and seizures/coda. [30]

When to see a doctor

1. Any increasing jaundice, dark urine, light-colored stools, itching - urgent. 2) Photosensitivity with blisters/scars, especially on the hands - see a dermatologist/hepatologist. 3) Sudden cyanosis with normal PaO₂ - go to the emergency department. 4) Signs of systemic iron overload (family history, hyperpigmentation, elevated ferritin) - see a hepatologist/hematologist. [31]

Diagnostics

Step 1. Basic blood screening: complete blood count, liver biochemistry (ALT, AST, ALP, GGT, albumin), total bilirubin, and fractionated bilirubin (total/direct). Fractionation will immediately differentiate hyperbilirubinemia into conjugated vs. unconjugated and narrow the search. [32]

Step 2. Instrumentally, as indicated: in case of conjugated hyperbilirubinemia - ultrasound of the hepatobiliary zone (primary visualization), if necessary, MRCP/ERCP; in case of iron overload - elastography/MRI-Fe of the liver; in case of skin photodiseases - dermatoscopy, skin biopsy as indicated. [33]

Step 3. Specific panels:

• If AHP is suspected, take a single urine sample at the time of symptoms for porphobilinogen and δ-aminolevulinic acid with correction for creatinine; if confirmed, perform molecular diagnostics (HMBS/CPOX/PPOX/ALAD). [34]
• Cutaneous porphyrias - spectrum of porphyrins in plasma/urine/feces for typing (characteristic PCT/EPP profiles). [35]
• Methemoglobinemia - gaseous blood with co-oximeria (gold standard), pulse oximetry is unreliable; simultaneously identify the provoking agent. [36]
• Iron overload - transferrin saturation, ferritin; genetics of HFE with high saturation. [37]
• Gilbert/UGT1A1 - as a rule, a clinic + laboratory is sufficient; genetics is not always needed. [38]

Step 4. Diagnostic pitfalls: “pure” abdominal pain with normal CT and hyponatremia – consider AHP; SpO₂ 85% with normal PaO₂ – look for dyshemoglobinemia; “blistering” photodermatosis in adulthood – optimally check porphyrins before biopsy. [39]

Table 6. Interpretation of tests for jaundice

Pattern	Bilirubin	ALT/AST	ALP/GGT	The next step
Unconjugated	↑ indirect	N	N	Hemolysis? UGT1A1? Drugs/fasting
Hepatocellular	Different	↑↑	↑/N	Viruses/drugs/autoimmunity; elastography
Cholestatic	↑ straight	N/↑	↑↑	Ultrasound→MRCP/ERCP

Differential diagnosis

• AHP vs. "acute abdomen": In AHP, pain is "out of proportion" to imaging findings; no peritoneal signs; porphyrin biomarkers are positive.[40]
• PCT vs. bullous dermatoses: PCT produces photoinduced blisters on the dorsum of the hands, hypertrichosis, characteristic uroporphyrin profile; bullous pemphigoid has a different immune pattern.[41]
• Methemoglobinemia vs. cardiopulmonary hypoxia: with metHb - normal PaO₂ and saturation gap, chocolate-colored blood; methylene blue quickly corrects symptoms (if there are no contraindications). [42]
• Gilbert vs. hemolysis: in Gilbert, reticulocytes/LDH/hemolysis markers are not elevated, liver enzymes are normal. [43]

Treatment

Treatment of acute hepatic porphyria attacks begins immediately after urine collection for δ-aminolevulinic acid and porphobilinogen: intravenous hematin/hemin 3-4 mg/kg for 4 days, glucose, elimination of triggers, pain and autonomic control, and correction of hyponatremia. In the long term, givosiran (an RNAi inhibitor of ALAS1) is used in patients with recurrent attacks; in randomized trials, it significantly reduces the frequency of attacks and hospitalizations. [44]

In porphyria cutanea tarda (PCT), the treatment strategy is aimed at iron depletion and elimination of liver factors: therapeutic bloodletting until ferritin levels are normalized and low-dose hydroxychloroquine therapy (microdoses) to mobilize porphyrins. Concurrent treatment includes treatment of underlying conditions (HCV, alcoholic hepatitis, etc.), photoprotection, and wound care. [45]

In erythropoietic protoporphyria (EPP), the basis is strict photoprotection and monitoring of liver function. Afamelanotide (implant) reduces photopain and increases permissible time in the sun; in severe hepatopathy, liver transplantation is considered, and sometimes plasmapheresis/hemosorption is used as a bridge. Promising molecules (e.g., bitopertine, a GlyT1 inhibitor) are in the clinical evaluation stage. [46]

Methemoglobinemia with symptoms and/or metHb levels usually ≥10% is treated with methylene blue (1-2 mg/kg intravenously), which rapidly restores the reduced form of heme; in G6PD deficiency, ascorbic acid is preferred; exchange transfusion is possible in refractory cases. Discontinuation of the causative agent (nitrates, dapsone, local anesthetics) is important. [47]

Sulfhemoglobinemia does not respond to methylene blue; treatment is elimination of the cause, and in severe cases, exchange transfusion. [48]

In Gilbert's syndrome, drug therapy is usually not required: it is sufficient to explain the benign nature of the condition, avoid fasting, and correct triggers; if anxiety about appearance is severe, non-drug approaches (regular meals, sleep, stress management) are discussed. Genetic testing for UGT1A1 for confirmation is not indicated for everyone. [49]

Iron overload/hemochromatosis is treated with regular bloodletting until ferritin reaches ~50-100 ng/ml, followed by maintenance procedures; in secondary hemosiderosis and the impossibility of bloodletting, iron chelators (deferasirox, etc.) are used. Screening for complications (liver, heart, endocrine system) is mandatory. [50]

Cutaneous hyper/hypomelanosis: melasma - photoprotection, topical depigmentants (hydroquinone, tretinoin, azelaic acid), chemical peels/lasers as indicated; vitiligo - topical steroids/calcineurin inhibitors, narrowband UVB therapy, repigmentation techniques in selected cases. For codes, see ICD-11 ED60/ED63. [51]

Neuronal ceroid lipofuscinoses (CLN2): cerliponase alfa (enzyme replacement therapy) has been available in children since 2017; in 2024, the indications were expanded to all children, including those <3 years old, which helps slow the loss of walking. Treatment is administered intraventricularly in specialized centers. [52]

Table 7. "What to prescribe and when"

Nosology	First line	Innovations/additions
AHP attack	Hemin/hematin, glucose, trigger release	Givosiran for prophylaxis
PCT	Phlebotomy, microdoses of hydroxychloroquine	Treatment of background (HCV), photoprotection
EPP	Photoprotection, liver monitoring	Afamelanotide; extracorporeal methods for hepatopathy
Methemoglobinemia	Methylene blue; cancellation of causes	Ascorbate, exchange transfusion/HBO as indicated
Hemochromatosis	Phlebotomy	Chelators (for secondary forms)
Vitiligo/melasma	Topical therapy + UV/photoprotection	Procedures/lasers for strict indications
CLN2	-	Cerliponase alfa

Prevention

Sun protection (clothing, high SPF) reduces phototoxicity in porphyria and melasma. Discontinuing potentially dangerous medications in patients with AHP/metHb predisposition and a sensible diet (avoiding fasting) in patients with Gilbert's syndrome reduce the risk of exacerbations. Genetic counseling is recommended in high-risk families (HFE, porphyria, UGT1A1). [53]

Forecast

Timely diagnosis (especially biochemical diagnostics at the onset of symptoms in AHP, co-oxygen testing in dyshemoglobinemia) and targeted prophylaxis dramatically improve quality of life and reduce hospitalizations. PCT is usually well controlled with phlebotomy and risk factor correction. In some patients with EPP, the risk of liver complications requires dynamic monitoring. In CLN2, access to enzyme replacement slows the loss of ambulation. [54]

FAQ

Is this a single disease or an umbrella of conditions?
It's an umbrella: from porphyria and jaundice to methemoglobinemia and pigmented dermatoses. The key is to correctly identify which pigment and at what stage of the pathway is "broken." [55]

What tests are most "decisive" in the acute onset of the disease?
For abdominal pain without findings, urine for PBG/δ-ALA (AHP). For "blue" skin and normal PaO₂, co-oxygenation (metHb). For jaundice, bilirubin fractions and liver enzymes. [56]

Is it possible to completely cure it?
Many conditions are manageable (PCT, hemochromatosis, Gilbert's disease). In AHP, a reduction in the frequency of attacks is achieved with givosiran. EPP does not "disappear," but afamelanotide significantly improves sun tolerance. [57]

What are the most common errors?
Late collection of biopsy material for AHP (when the parameters have already returned to normal), attempting to treat sulfhemoglobinemia with methylene blue, and excessive radiation exposure instead of a basic ultrasound for cholestasis. [58]