Porto-Sinusoidal Vascular Disease in Congenital Erythropoietic Porphyria Needing Liver Transplantation

ABSTRACT

Porphyria caused by inherited disorders in heme biosynthesis can lead to accumulation of porphyrins in various organs. Liver involvement due to porphyria mostly results in cholestasis leading to liver cirrhosis or hepatocellular carcinoma. Congenital erythropoietic porphyria (CEP), a rare porphyria due to deficiency of uroporphyrinogen III synthase, mostly results in cutaneous manifestations. There are reports of liver involvement including varying degree of fibrosis in patients with CEP. We report a unique case of a patient with CEP who developed porto-sinusoidal vascular disease with complications of portal hypertension that necessitated liver transplantation.

INTRODUCTION

Porphyria consists of a group of inherited disorders which result in abnormality of one of the 8 enzymes involved in heme biosynthesis.¹ About 80% of heme biosynthesis occur in bone marrow and the rest 20% in the liver. Porphyria can be either hepatic or erythropoietic, depending on primary site of overproduction and accumulation of the porphyrin precursors.² Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive disease due to uroporphyrinogen III synthase (UROS) deficiency.³ More than 50 pathogenic mutations in UROS have been identified.⁴ Lack of UROS results in accumulation of substrate hydroxymethylbilane, which nonenzymatically forms a nonfunctional product, uroporphyrinogen I and then coproporphyrinogen I and eventually a pathogenic porphyrin isomer, uroporphyrin I and coproporphyrin I.⁵ These porphyrins can accumulate in multiple organs, most commonly in skin leading to cutaneous photosensitivity and photo mutilation. Other symptoms include chronic hemolytic anemia, abdominal pain, nausea, and vomiting.⁶ Liver involvement is also described in CEP due to accumulation of porphyrins leading to fibrosis.^7,8 However, there are no reports of porto-sinusoidal vascular disease (PSVD) with portal hypertensive complications requiring liver transplantation (LT) in patients with CEP.

CASE REPORT

A 21-year-old woman with a history of CEP presented for refractory ascites evaluation. She was diagnosed with CEP at the age of 1 month, initially had hyperbilirubinemia due to hemolysis required phototherapy resulting in skin photo mutilation and subsequent scarring requiring skin grafting. Since then, she used precautions to avoid sun exposure, which prevented acute porphyria attacks. She required less than 15 units of blood transfusion over the years and was not on medications chronically. At the age of 20 years, she presented with sudden onset hematemesis and abdominal distension. Hemoglobin at presentation was 2.9 g/dL (baseline hemoglobin 9 g/dL), required 5 units of red cell transfusion. Esophagogastroduodenoscopy revealed esophageal varices with signs of active bleeding, which were banded. At the same time, she was also found to have ascites and underwent paracentesis with 4.5 L of straw-colored fluid removal. Serum-ascites albumin gradient of 1.5 g/dL was consistent with portal hypertension. She had no family history of liver disease, did not drink alcohol, or used intravenous drugs. She did not use supplements, toxins, or any non-US Food and Drug Administration (FDA)-approved treatment of CEP. Comprehensive liver disease evaluation including workup for all viral hepatitis, Wilson disease, hemochromatosis, and all autoimmune hepatitis serologies were negative. Percutaneous liver biopsy revealed obliterative portal venopathy (OPV) with mild inflammation, nodular regeneration, bridging fibrosis, and pigment accumulation in the Kupffer cells. She was started on carvedilol for variceal prophylaxis, furosemide, and spironolactone for ascites management. Despite adhering to salt restriction and escalating doses of diuretics to maximum tolerable dose, she required paracentesis with 5 L of ascitic fluid drainage every 2–3 weeks.

During the visit, physical examination revealed conjunctival pallor, diffuse atrophic scarring in sun-exposed areas, and abdominal distension with shifting dullness and fluid thrill. Laboratory evaluation showed hemoglobin 9 g/dL, platelet count 274 × 10⁹/L, sodium 132 mEq/L, creatinine 0.71 mg/dL, albumin 3.3 g/dL, aspartate aminotransferase 187 U/L, alanine aminotransferase 58 U/L, alkaline phosphatase 171 U/L, total bilirubin 0.6 mg/dL, ferritin 217 mcg/L, prothrombin time 14.2 second, and iron 39 mcg/dL. Model for End-Stage Liver Disease-Sodium (MELD-Na) score was 7. Whole-genome sequencing revealed heterozygous pathogenic variants in UROS (p.Gly225Ser and p.Ser212Pro), but no known genetic causes of PSVD were identified. Magnetic resonance imaging revealed hepatomegaly (20 cm) with irregular surface, splenomegaly (22.9 cm), moderate to severe ascites, and no portal or hepatic vein thrombosis (Figure 1).

Figure 1.

Magnetic resonance imaging of the liver—coronal view showing hepatosplenomegaly with moderate to severe ascites (white arrows).

Six months later, given refractory ascites she underwent transjugular intrahepatic portosystemic shunt (TIPS), during which the hepatic venous portal gradient was found to be 15 mm Hg and 8 mm TIPS was placed which reduced the hepatic venous portal gradient to 8 mm Hg. Two months later, ultrasound showed inadequate flow through the TIPS and developed recurrent ascites. Because of ongoing decompensation, she underwent unrelated living donor LT. Histological evaluation of liver explant revealed OPV with nodular regeneration and bridging fibrosis (Figure 2). Multiple infarcted regenerative nodules were also noted. Two months out of liver transplantation, she is doing well and is undergoing evaluation for allogenic hematopoietic stem cell transplantation (HSCT).

Figure 2.

Histopathology. (A) Many small portal areas lack a clear portal vein (Hematoxylin and eosin stain, 200×). (B) Bridging fibrosis (Masson trichrome, 40×). (C) Nodular regeneration is present, not necessarily associated with fibrosis (Reticulin, 40×). (D) Aberrant expression of CD34 is seen in sinusoidal endothelial cells (100×).

DISCUSSION

Previous reports on hepatic involvement in CEP have highlighted features such as hepatomegaly, varying degrees of fibrosis, and cirrhosis.^6,7 A noteworthy case even reported fatal liver failure and hepatorenal syndrome, revealing sinusoidal congestion, dilatation, and patchy fibrosis during autopsy, although cirrhosis and porphyrin deposition were notably absent.⁸ However, the underlying pathophysiology for hepatic involvement in CEP remains poorly understood. While nodular regeneration has been observed in other porphyria types, there are no reports of PSVD due to CEP.⁹ We report a patient with liver biopsy revealing typical features of PSVD including OPV and incomplete cirrhosis.¹⁰ She had thorough evaluation for known causes of PSVD, before considering CEP as a potential etiology.^10,11

All organs are susceptible to toxic effects of porphyrin, including the liver. In CEP, a common hepatic manifestation is elevated liver-associated enzymes, which improve post-HSCT. However, caution is needed when considering HSCT in CEP patients with hepatic involvement, as liver failure post-HSCT has been reported in cases with underlying fibrosis.⁷ Unfortunately, our patient lacked regular follow-up preceding the decompensation episode, and no liver-associated enzymes reports were available.

CEP is a rare form of erythropoietic porphyria. A more common form of erythropoietic porphyria is erythropoietic protoporphyria, where 5%–20% of patients develop liver disease.¹² Liver involvement in erythropoietic protoporphyria is due to protoporphyrin IX accumulation in the bile canaliculi and ductules leading to cholestasis and liver cirrhosis.¹³ Similar to our patient, those with end-stage liver disease secondary to porphyria should undergo LT. However, unlike cirrhosis, MELD scores may not be reliable to determine priority for LT in PSVD.^14,15 Importantly, LT does not address the underlying heme synthetic defect, necessitating allogenic HSCT for a definitive cure and to prevent disease recurrence.^16–18 While undergoing LT, caution should be exercised regarding the use of specific UV light filter blocks to avoid phototoxic injury in these patients.¹⁹

In conclusion, PSVD can indeed manifest in CEP, emphasizing the need for monitoring of hepatic function in affected patients. The underlying pathophysiology of hepatic involvement in porphyria requires further exploration.

DISCLOSURES

Author contributions: H. Gopalakrishna wrote the manuscript. H. Gopalakrishna, M. Mironova, S. Malik, A. Faust, N. Khurram, C. Koh, DE Kleiner, and T. Heller clinically evaluated the patient and edited the manuscript. T. Heller is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.