The porphyrias are a group of rare metabolic disorders that result from defects in heme biosynthesis. Erythropoietic protoporphyria (EPP) is the most common inherited porphyria in children and is diagnosed in most individuals after the onset of cutaneous manifestations. Hepatobiliary disease affects the minority of individuals with EPP and usually manifests in patients with an established diagnosis of EPP. We report on a classic but rare case of EPP that masqueraded as cholestasis. An 8-year-old boy was referred to the Hepatology Clinic after an abrupt onset of jaundice with a longstanding history of dermatitis. The diagnosis of EPP was established with liver biopsy, which revealed dense, dark-brown pigment in hepatocytes and Kupffer cells that, on polarization, displayed bright-red birefringence and centrally located Maltese crosses. Plasma total porphyrins and erythrocyte protoporphyrin were elevated and confirmed a diagnosis of EPP. We hope to raise awareness of this diagnosis among pediatricians, hepatologists, and pathologists and increase the consideration of EPP in patients with cholestatic liver disease and chronic dermatitis.
- ALT —
- alanine aminotransferase
- AST —
- aspartate aminotransferase
- EPP —
- erythropoietic protoporphyria
- FECH —
- HDL —
- high-density lipoprotein
The porphyrias are a group of rare metabolic disorders that result from a primary hereditary deficiency in 1 of 8 enzymes involved in heme biosynthesis. Erythropoietic protoporphyria (EPP), with a reported prevalence of 1 in 75 000 to 1 in 200 000,1 is the most common porphyria in children.2,3 The classic form results from a mutation in the ferrochelatase (FECH) gene and has both autosomal recessive and dominant patterns of inheritance with a high degree of allelic heterogeneity and incomplete penetrance, allowing for significant variability in clinical presentation. The X-linked dominant protoporphyria may also give rise to a similar phenotype and results from mutations of the aminolevulinic acid synthase 2 gene.4 Some of the variability in presentation (in particular, the age at diagnosis) has been attributed to delayed presentation of subtle and nonspecific symptoms.1,5
The skin manifestations in the majority of individuals with EPP are confined to sun-exposed areas and worsen during summer months. Cutaneous symptoms are attributed to an accumulation of protoporphyrin in the upper dermis, resulting in acute photosensitivity.6 Patients characteristically refer to skin pain, burning, stinging, and itching during sun exposure, which are often accompanied by erythema and swelling. Chronic changes include lichenification manifested as grooving around the lips, a loss of lunulae of the nails, postinflammatory hypopigmentation and hyperpigmentation, and scarring.
Hepatobiliary disease occurs in up to 20% of patients with EPP; however, only 5% develop advanced liver disease with cholestasis and even liver failure.1,3,6,7 The diagnosis of EPP is typically already established by the time liver disease manifests. It is rare that patients with EPP first present with symptoms of liver disease; however, the skin lesions may not be initially recognized as manifestations of EPP.8 We report on an 8-year-old boy who presented with chronic cutaneous changes and acute onset of jaundice and hepatitis whose diagnosis of EPP was established on liver biopsy. This unusual presentation highlights the need for pediatricians, hepatologists, and pathologists to consider EPP in children with unrecognized chronic dermatitis and cholestasis.
An 8-year-old, African American boy presented with acute onset of scleral icterus, jaundice, and worsening pruritus. The patient did not report abdominal pain, nausea, or vomiting. His past medical history was significant for a longstanding pruritic facial rash with blistering, unexplained hypo- and/or hyperpigmentation, and an intermittent burning sensation in his toes during the summer. He also had atrial and ventricular septal defects with aortic arch hypoplasia and asthma. Six weeks before, the patient reported that his fingernails became loose and fell out; concomitantly, he also developed intense pruritus of the hands and feet. His mother noted that except for the jaundice, these symptoms seemed to occur every summer. His height for age was at the 21st percentile, and both weight for age and BMI were at the 9th percentile.
Physical examination was remarkable for a thin but healthy-appearing individual in no acute distress. He had prominent scleral icterus. His liver was palpable at 3.5 cm below the right costal margin, and a spleen tip was also palpable. He had healed blisters, notable scabbing, and hyper- and/or hypopigmented freckling on his face, arms, hands, and feet. Scarring was evident in addition to generalized jaundice (Fig 1).
Complete blood cell count results were normal. Serum biochemistry revealed the following: aspartate aminotransferase (AST) of 79 U/L (normal, 12–32 U/L); alanine aminotransferase (ALT) of 64 U/L (normal, 8–30 U/L); gamma-glutamyl transferase of 98 U/L (normal, 3–22); total bilirubin of 6.8 mg/dL (normal, 0.2–0.8 mg/dL) with direct bilirubin of 4.0 mg/dL (≤0.2 mg/dL); alkaline phosphatase of 228 U/L (normal, 47–324 U/L); and albumin of 4.7 g/dL (normal, 3.6–5.1 g/dL). A viral hepatitis panel was reactive for total hepatitis A antibodies (nonreactive for hepatitis A immunoglobulin M) but otherwise normal. Additional workup included antinuclear, F-actin, and liver-kidney microsomal antibodies; total immunoglobulin G; Epstein-Barr virus immunoglobulin M and/or immunoglobulin G; ceruloplasmin; and prothrombin and/or international normalized ratio. All were normal. A nonfasting lipid profile at diagnosis revealed a total cholesterol of 178 mg/dL (normal, 125–170), high-density lipoprotein (HDL) of 6 mg/dL (normal, 38–76), triglyceride of 232 (normal range, 30–104), low-density lipoprotein cholesterol of 126 mg/dL (normal, <110 mg/dL), and a cholesterol and/or HDL total ratio of 29.7 (normal <5.0).
The patient’s abdominal ultrasound revealed an enlarged liver measuring 14.9 cm in the maximal craniocaudal dimension. The liver parenchyma had a normal sonographic appearance without intra- or extrahepatic biliary duct dilatation. The gallbladder and common bile duct were unremarkable, and there was no ascites. A Doppler evaluation showed normal hepatic vasculature with normal directional flow and waveforms.
The hepatologist’s differential diagnosis included non–A-C viral hepatitis, autoimmune liver disease, primary sclerosing cholangitis, drug-induced liver injury, Alagille syndrome, and progressive familial intrahepatic cholestasis, and recommended liver biopsy.
A core liver biopsy (needle) revealed a focal accumulation of dense, dark-brown pigment within hepatocytes and Kupffer cells (Fig 2). With polarized light, these deposits were found to be a bright-red birefringent with centrally located Maltese crosses, which are features that are characteristic of EPP. A trichrome stain showed a fibrous expansion of portal tracts with incomplete bridging and pericentral fibrosis, which is consistent with Metavir stage 3 fibrosis. Portal tracts contained a mild lymphohistiocytic inflammatory infiltrate in addition to the macrophages containing the dense birefringent material. Mild cholangiolar proliferation was seen in portal areas, highlighted by cytokeratin 7 (Monoclonal antibody OV-TL 12/30; Dako, Glostrup Municipality, Denmark). In addition, cytokeratin 7 showed strong aberrant expression in hepatocytes. Immunohistochemistry demonstrated an expression of multidrug resistance protein 3 (P3II-26; Alexis Biochemicals, San Diego, CA) and bile salt export pump (F-6; Santa Cruz Biotechnology, Dallas, TX) in the biliary canaliculi, excluding the diagnostic possibility of progressive familial intrahepatic cholestasis types 2 and 3. No hemosiderin or copper was demonstrable by special stains. A mild accumulation of α-1-antitrypsin (Dako) was observed in Kupffer cells but not in hepatocytes. An ultrastructural examination revealed numerous slender, electron-dense, straight or curved pigment crystals within Kupffer cells and hepatocytes corresponding to the dense birefringent material (Fig 2), which are consistent with protoporphyrin.
This led to the measurement of plasma erythrocyte protoporphyrin, which was 932 μmol/mol of heme (reference, <70) and a total porphyrin level of 1779.2 μg/L (normal, 1.0–5.6).
The patient was started on 20 mg/kg per day per os twice daily of ursodeoxycholic acid, and subsequently, 2 g per os twice daily of cholestyramine was added (see the discussion for putative indications). The parents were told that there was no effective way of lowering circulating porphyrin levels in individuals with EPP. We recommended a healthy avoidance of both sunlight and fluorescent light as much as possible. The patient was prescribed oral β-carotene capsules (90 mg per day) to neutralize the reactive chemical compounds formed by protoporphyrin in hopes of lessening his symptoms of photosensitivity and 400 IUs daily of vitamin E to promote wound healing and for its antioxidant effects.
The patient was temporarily lost to follow-up after diagnosis but presented to the hospital 6 months later with influenza type A. The patient had gained 0.7 kg since his diagnosis. AST, ALT, and gamma-glutamyl transferase were 598, 543, and 57 IU/L, respectively, with conjugated bilirubin of 0.1 mg/dL after 2 months of noncompliant therapy with ursodiol and fat-soluble vitamins. Serum bile acid levels were not checked. Medications to treat EPP were restarted. One week later, AST and ALT were decreased to 119 and 328 U/L, respectively, with a conjugated bilirubin of 0 mg/dL. Vitamin D level was not assessed on admission, but it was assessed 13 months after diagnosis: 25-hydroxy vitamin D was 29 ng/mL (normal range, 30–100 ng/mL).
We report on an unusual presentation of EPP, which was unsuspected despite long-standing photosensitive dermatitis. The diagnosis was ultimately established by liver biopsy during an evaluation of new-onset cholestasis with mild hepatitis and notable hepatomegaly. EPP is a rare disease, and unless clinically suspected, it can go undiagnosed for a long time. Wahlin et al9 reported that the diagnosis of EPP is challenging, and the mean lapse of time between debut of symptoms and diagnosis is between 10 and 20 years. In our case, the patient came to our hospital with jaundice and hepatomegaly without evidence of biliary obstruction by imaging, triggering the liver biopsy. The patient’s hyper- and hypopigmented scars on his face, ears, and arms were initially unrecognized as characteristic of EPP. The diagnosis of EPP was finally suspected from our systematic histopathologic evaluation of the biopsy, which prompted a reassessment of the nature of the cutaneous lesions.
The diagnostic features of EPP in the liver are the presence of dense, dark-brown pigment within hepatocytes and Kupffer cells. When polarized, the pigment displays characteristic bright-red birefringence and a centrally located Maltese cross. This case also demonstrated features of cholestasis: cholangiolar proliferation and an aberrant expression of cytokeratin 7 in hepatocytes.
The liver is involved in the excretion of protoporphyrin into bile, and the pathogenesis of EPP-associated liver disease at least partially involves the precipitation of insoluble protoporphyrin in bile canaliculi.6,10 This results in functional obstruction that is partially responsible for these latter histopathologic changes. High plasma porphyrin and high erythrocyte protoporphyrin levels are confirmatory.
Jaundice was likely due to the precipitation of insoluble protoporphyrin in bile canaliculi and protoporphyrin-induced oxidative stress, which is the result of excess unmetabolized protoporphyrin interacting with the hepatocellular membrane and inducing impaired function of the sodium potassium-ATPase pump within the membrane. The accumulation of excess protoporphyrin that does not undergo biliary excretion leads to cholestasis and further reduces the excretion of protoporphyrin.6,11 These changes lead to hepatic inflammation and progressive liver disease. Thus, the biochemical features and histologic appearance of cholestasis were not due to cholelithiasis. Canalicular cholestasis, as suggested by Phillips et al,12 may be the result of interference with bile canaliculi contractility, an observation that is based on the interference of pericanalicular actin by cytochalasin.12 Aberrant hepatocyte expression of cytokeratin 7 can be seen in ductopenias and/or interlobular bile duct injury and cholestasis of various etiologies.13 Notably, this patient also had elevated plasma triglycerides and low HDL, which is well reported in EPP.14 As previously mentioned, a deficiency of the mitochondrial enzyme FECH causes EPP, and altered lipid metabolism may contribute to hepatobiliary disease. In homozygous FECH-FECH mice, hyperlipidemia with reduced HDL is accompanied by increased hepatobiliary bile salts.15 Bile salt secretion triggers the secretion of phospholipids and cholesterol into bile, and the ability of bile salts to stimulate lipid secretion depends on the activity of multidrug resistance–associated protein 2 P-glycoprotein, a phosphatidyl translocation glycoprotein.16 It has been shown that increased hepatic bile salt flux in FECH-FECH mice is also associated with increased multidrug resistance–associated protein 2 expression.17 Yet, the amount of biliary cholesterol and phospholipids relative to that of bile salts is reduced in these animals, indicating that the coupling between the secretion rates of these bile constituents is disrupted.17 In humans, it is unknown if this is responsible for the biliary fibrosis and bile duct proliferation seen in EPP.
Although abnormal erythrocyte protoporphyrin and total plasma porphyrins may be diagnostic of the disease, children with hepatosplenomegaly or cholestatic hepatitis merit a liver biopsy, which is the gold standard to determine the degree of liver injury and fibrosis. Noninvasive markers of fibrosis, such as the AST to Platelet Ratio Index, FibroTest, or Enhanced Liver Fibrosis blood test, may be helpful but have not been validated in this rare disease. EPP hepatobiliary disease may present with a variety of clinical manifestations. Cholelithiasis frequently occurs because insoluble protoporphyrin within bile serves as a nidus for stone formation. Protoporphyrin hepatopathy is rare, occurring in <5% of patients with protoporphyrias,1 who often present with an acute and rapidly progressive form of liver disease with severe right-upper quadrant pain, jaundice, nausea, and vomiting.18 Such patients may already have underlying chronic liver disease or cirrhosis with splenomegaly or other evidence of portal hypertension (eg, esophageal varices and ascites).19 Hepatopathy may also lead to worsening skin pathology as greater amounts of porphyrins accumulate. There are currently no reliable prognostic markers to identify patients who are at risk for hepatic failure, nor is there a consensus for surveillance protocols. More severe liver involvement has been associated with the presence of null mutations, autosomal-recessive disease, and aminolevulinic acid synthase 2 gene mutations.3,4
This case illustrates that undiagnosed, chronic, recurring skin manifestations of EPP may precede the development of clinically apparent liver disease, confirming that a delay in diagnosis may be due to the often subtle and unrecognized cutaneous symptoms.1,5 However, a prolonged delay prevents early recognition and treatment of hepatobiliary disease, which may significantly impact quality of life. End-stage liver disease may be accompanied by motor neuropathy similar to that seen in acute porphyrias.8
Treatment approaches for progressive liver disease in EPP have had only modest efficacy in controlling disease progression until recently. Ursodeoxycholic acid may help promote the biliary excretion of protoporphyrin.20 Cholestyramine is useful in interrupting the enterohepatic circulation of protoporphyrin.21 N-acetyl cysteine, similar to vitamin E,22 may also theoretically attenuate oxidative and nitrosative stress in liver injury caused by protoporphyrin. β-carotene can be used as a protective measure to lessen symptoms of photosensitivity by neutralizing the reactive chemical compounds that are formed by protoporphyrin. Liver transplantation restores normal liver function, including the hepatic excretion of protoporphyrin, but it does not correct the metabolic abnormality in the bone marrow, which continues to produce excessive amounts of protoporphyrin.23 Parenteral iron, red blood cell transfusion, and infusion of hematin are all methods that are employed to reduce protoporphyrin production, whereas plasmapheresis and extracorporeal albumin dialysis may reduce circulating protoporphyrin levels, particularly after liver transplantation.24 Recent literature shows promising effects of cimetidine in the management of patients with EPP in that it reduced skin photosensitivity and improved liver function.25 Other researchers have shown that afamelanotide improves tolerance to sun exposure and prevents phototoxicity in adult patients with EPP.26,27
A growing number of patients with EPP-associated liver failure have undergone liver transplantation. Unfortunately, there is a high risk for disease recurrence in the allograft liver.
Molecular studies are important to confirming the diagnosis of autosomal-recessive and X-linked–dominant EPP and for genetic counseling. This should be completed first in a person who is known to have the disease, and the information about the mutations in that individual should be used to guide the testing of family members. Carrier genetic testing is recommended for asymptomatic, at-risk family members. Prenatal testing is recommended for pregnant women who are at increased risk if the pathogenic variant in the family has been identified.28
We report on a case of EPP in an 8-year-old child with a longstanding history of unrecognized cutaneous photosensitivity presenting as new-onset cholestatic liver disease. The diagnosis was first established on liver biopsy instead of the traditional clinical laboratory tests: abnormal erythrocyte protoporphyrin and total plasma porphyrins. We hope to alert pediatricians, hepatologists, and pathologists to consider EPP in patients who present with a recent onset of cholestasis and chronic cutaneous symptoms.
We acknowledge Dr Milton J. Finegold for his assistance in editing our article. We also acknowledge Peggy Kellum and Karen Prince at Texas Children’s Hospital for their contribution to the formatting of this article.
- Accepted May 16, 2017.
- Address correspondence to Norma M. Quintanilla, MD, Department of Pathology, Texas Children’s Hospital, 6621 Fannin St, Suite AB195.23, Houston, TX 77030. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2018 by the American Academy of Pediatrics