Case Report Annals of Clinical Biochemistry 2015, Vol. 52(3) 407–412 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0004563214557568 acb.sagepub.com
Hepatocellular carcinoma in variegate porphyria: a case report and literature review Ahai Luvai1, Wycliffe Mbagaya1, Deepa Narayanan1, Tim Degg1, Giles Toogood2, Judith I Wyatt3, Daniel Swinson4, Claire J Hall5 and Julian H Barth1
Abstract Variegate porphyria is an autosomal dominant acute hepatic porphyria characterized by photosensitivity and acute neurovisceral attacks. Hepatocellular carcinoma has been described as a potential complication of variegate porphyria in case reports. We report a case of a 48-year-old woman who was diagnosed with hepatocellular carcinoma following a brief history of right upper quadrant pain which was preceded by a few months of blistering lesions in sun-exposed areas. She was biochemically diagnosed with variegate porphyria, and mutational analysis confirmed the presence of a heterozygous mutation in the protoporphyrinogen oxidase gene. Despite two hepatic resections, she developed pulmonary metastases. She responded remarkably well to Sorafenib and remains in remission 16 months after treatment. A review of the literature revealed that hepatocellular carcinoma in variegate porphyria has been described in at least eight cases. Retrospective and prospective cohort studies have suggested a plausible association between hepatocellular carcinoma and acute hepatic porphyrias. Hepatic porphyrias should be considered in the differential diagnoses of hepatocellular carcinoma of uncertain aetiology. Patients with known hepatic porphyrias may benefit from periodic monitoring for this complication.
Keywords Cancer, inborn errors of metabolism, liver disease Accepted: 20th September 2014
Introduction The porphyrias are a group of heterogeneous disorders resulting from acquired or genetically determined enzyme deficiencies of the haem biosynthetic pathway. Variegate porphyria (VP; OMIM 176200), an autosomal dominantly inherited porphyria, is consequent to a partial deficiency of protoporphyrinogen oxidase (PPOX), the penultimate enzyme in haem biosynthesis.1 In common with hereditary coproporphyria (HCP), it may present with acute neurovisceral attacks and cutaneous involvement with approximately 60% of patients with VP presenting with skin lesions, 20% with acute neurovisceral attacks alone and 20% with both
these manifestations. VP is about one-third as prevalent as acute intermittent porphyria (AIP) in most European countries.2 In Europe, the VP population is 1 Department of Clinical Biochemistry, St James University Hospital, Leeds, UK 2 Department of Hepatobiliary Surgery, St James University Hospital, Leeds, UK 3 Department of Histopathology, St James University Hospital, Leeds, UK 4 Department of Oncology, St James University Hospital, Leeds, UK 5 Haematology Department, Harrogate District Hospital, Harrogate, UK
Corresponding author: Ahai Luvai, Hull Royal Infirmary, Pathology Building, Anlaby Road, Hull HU3 2JZ, UK. Email: [email protected]
Downloaded from acb.sagepub.com at UNIV OF PITTSBURGH on June 2, 2015
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genetically heterogeneous with low penetrance, and only a minority of patients experience recognizable symptoms potentially leaving many at risk of longterm sequelae. Hepatocellular carcinoma (HCC) has been reported as a complication of VP.3 We discuss the case history of a patient with HCC manifesting within a few months of her first cutaneous lesions of undiagnosed VP.
Case history A 48-year-old Caucasian woman presented to her general practitioner (GP) with dyspepsia and right upper quadrant abdominal pain. A few months prior to this, she had noticed blistering lesions on the dorsa of both hands. She was otherwise fit and well with no active medical problems. There were no risk factors for liver disease, i.e. minimal alcohol intake, no recent foreign travel, no previous blood transfusions and no significant family history. Clinical examination revealed right upper quadrant fullness but was unremarkable otherwise. An ultrasound scan of the liver revealed a 14-cm predominantly echogenic heterogeneous mass in the liver with limited blood flow. The spleen, pancreas, gallbladder, kidneys and abdominal aorta were normal. A follow on computerized tomography (CT) scan delineated a well-defined mass in the right hepatic lobe measuring 11 14 cm in maximal axial dimension. The rather chaotic internal enhancement characteristics necessitated further imaging by magnetic resonance imaging (MRI), and this suggested the presence of HCC.4 The serum alpha fetoprotein (AFP) was >300 kU/L (reference interval: 3–8 kU/L, Immulite). Human Haemochromatosis Protein (HFE) gene testing found that she was a C282Y heterozygote with normal ferritin and transferrin saturation. Serology testing for infective and autoimmune liver disease was negative. She was referred to the hepatobiliary surgeons. In view of the cutaneous lesions, she was also initially referred to dermatology and subsequently to the specialist porphyria clinic.
Investigation and management Porphobilinogen and porphyrin methods Total urine porphyrins were measured spectrofluorimetrically after oxidation of any porphyrinogen. Total faecal porphyrins were measured spectrophotometrically on the Hitachi U-2001 after acid extraction of porphyrins from faeces. Porphyrin isomers were separated and measured directly from acidified urine or extracted faeces by reversed-phase gradient elution chromatography on the Shimadzu high-performance liquid chromatography (HPLC) system. Plasma porphyrins were qualitatively scanned on the Hitachi
F-4500 fluorescence spectrophotometer. Free porphyrins were extracted from plasma and analysed fluorimetrically using an excitation scan. The plasma porphyrin concentration was calculated using a ‘GWBASIC’ computer programme which corrects for background interference. The calibration material was sourced from independent suppliers, and the excitation and emission wavelength accuracy was checked weekly to ensure optimum performance using the sharp spectral line of the xenon lamp.
Porphobilinogen and porphyrin results The initial porphyrin screen included urine, faeces and plasma samples which showed: . Urine porphyrin/creatinine ratio: 146.1 nmol/mmol (
Hepatocellular carcinoma in variegate porphyria: a case report and literature review Ahai Luvai1, Wycliffe Mbagaya1, Deepa Narayanan1, Tim Degg1, Giles Toogood2, Judith I Wyatt3, Daniel Swinson4, Claire J Hall5 and Julian H Barth1
Abstract Variegate porphyria is an autosomal dominant acute hepatic porphyria characterized by photosensitivity and acute neurovisceral attacks. Hepatocellular carcinoma has been described as a potential complication of variegate porphyria in case reports. We report a case of a 48-year-old woman who was diagnosed with hepatocellular carcinoma following a brief history of right upper quadrant pain which was preceded by a few months of blistering lesions in sun-exposed areas. She was biochemically diagnosed with variegate porphyria, and mutational analysis confirmed the presence of a heterozygous mutation in the protoporphyrinogen oxidase gene. Despite two hepatic resections, she developed pulmonary metastases. She responded remarkably well to Sorafenib and remains in remission 16 months after treatment. A review of the literature revealed that hepatocellular carcinoma in variegate porphyria has been described in at least eight cases. Retrospective and prospective cohort studies have suggested a plausible association between hepatocellular carcinoma and acute hepatic porphyrias. Hepatic porphyrias should be considered in the differential diagnoses of hepatocellular carcinoma of uncertain aetiology. Patients with known hepatic porphyrias may benefit from periodic monitoring for this complication.
Keywords Cancer, inborn errors of metabolism, liver disease Accepted: 20th September 2014
Introduction The porphyrias are a group of heterogeneous disorders resulting from acquired or genetically determined enzyme deficiencies of the haem biosynthetic pathway. Variegate porphyria (VP; OMIM 176200), an autosomal dominantly inherited porphyria, is consequent to a partial deficiency of protoporphyrinogen oxidase (PPOX), the penultimate enzyme in haem biosynthesis.1 In common with hereditary coproporphyria (HCP), it may present with acute neurovisceral attacks and cutaneous involvement with approximately 60% of patients with VP presenting with skin lesions, 20% with acute neurovisceral attacks alone and 20% with both
these manifestations. VP is about one-third as prevalent as acute intermittent porphyria (AIP) in most European countries.2 In Europe, the VP population is 1 Department of Clinical Biochemistry, St James University Hospital, Leeds, UK 2 Department of Hepatobiliary Surgery, St James University Hospital, Leeds, UK 3 Department of Histopathology, St James University Hospital, Leeds, UK 4 Department of Oncology, St James University Hospital, Leeds, UK 5 Haematology Department, Harrogate District Hospital, Harrogate, UK
Corresponding author: Ahai Luvai, Hull Royal Infirmary, Pathology Building, Anlaby Road, Hull HU3 2JZ, UK. Email: [email protected]
Downloaded from acb.sagepub.com at UNIV OF PITTSBURGH on June 2, 2015
408
Annals of Clinical Biochemistry 52(3)
genetically heterogeneous with low penetrance, and only a minority of patients experience recognizable symptoms potentially leaving many at risk of longterm sequelae. Hepatocellular carcinoma (HCC) has been reported as a complication of VP.3 We discuss the case history of a patient with HCC manifesting within a few months of her first cutaneous lesions of undiagnosed VP.
Case history A 48-year-old Caucasian woman presented to her general practitioner (GP) with dyspepsia and right upper quadrant abdominal pain. A few months prior to this, she had noticed blistering lesions on the dorsa of both hands. She was otherwise fit and well with no active medical problems. There were no risk factors for liver disease, i.e. minimal alcohol intake, no recent foreign travel, no previous blood transfusions and no significant family history. Clinical examination revealed right upper quadrant fullness but was unremarkable otherwise. An ultrasound scan of the liver revealed a 14-cm predominantly echogenic heterogeneous mass in the liver with limited blood flow. The spleen, pancreas, gallbladder, kidneys and abdominal aorta were normal. A follow on computerized tomography (CT) scan delineated a well-defined mass in the right hepatic lobe measuring 11 14 cm in maximal axial dimension. The rather chaotic internal enhancement characteristics necessitated further imaging by magnetic resonance imaging (MRI), and this suggested the presence of HCC.4 The serum alpha fetoprotein (AFP) was >300 kU/L (reference interval: 3–8 kU/L, Immulite). Human Haemochromatosis Protein (HFE) gene testing found that she was a C282Y heterozygote with normal ferritin and transferrin saturation. Serology testing for infective and autoimmune liver disease was negative. She was referred to the hepatobiliary surgeons. In view of the cutaneous lesions, she was also initially referred to dermatology and subsequently to the specialist porphyria clinic.
Investigation and management Porphobilinogen and porphyrin methods Total urine porphyrins were measured spectrofluorimetrically after oxidation of any porphyrinogen. Total faecal porphyrins were measured spectrophotometrically on the Hitachi U-2001 after acid extraction of porphyrins from faeces. Porphyrin isomers were separated and measured directly from acidified urine or extracted faeces by reversed-phase gradient elution chromatography on the Shimadzu high-performance liquid chromatography (HPLC) system. Plasma porphyrins were qualitatively scanned on the Hitachi
F-4500 fluorescence spectrophotometer. Free porphyrins were extracted from plasma and analysed fluorimetrically using an excitation scan. The plasma porphyrin concentration was calculated using a ‘GWBASIC’ computer programme which corrects for background interference. The calibration material was sourced from independent suppliers, and the excitation and emission wavelength accuracy was checked weekly to ensure optimum performance using the sharp spectral line of the xenon lamp.
Porphobilinogen and porphyrin results The initial porphyrin screen included urine, faeces and plasma samples which showed: . Urine porphyrin/creatinine ratio: 146.1 nmol/mmol (
