A 37-Year-Old Male with Hepatomegaly, Neurologic and Skin Involvement Associated with Elevated Urinary Porphyrin Excretion

CASE REPORT

A 37-year-old white male building contractor presented to the Mount Sinai Medical Center Liver Diseases out-patient unit in May 2000, seeking confirmation of a diagnosis of hereditary coproporphyria. He had been in good health until the age of 27, when he experienced the sudden onset of a severe headache. He was managed in the neurosurgical intensive care unit at a local hospital and was diagnosed as having had a subarachnoid hemorrhage on the basis of xanthochromic cerebrospinal fluid, although a cerebral angiogram was negative for an aneurysm. Following this, he had recurrent migraine-like headaches for approximately 6 months, for which he was treated with ergotamine preparations. The headaches eventually subsided spontaneously, and he remained well for a number of years.

Approximately 2 years prior to this visit, he began to experience severe fatigue, disturbed sleep patterns, and episodes of epigastric and left upper quadrant pain. He frequently was nauseated on awakening in the morning, and-especially on Sundays-often had several bouts of morning vomiting. He developed an intermittent tremor of his hands, so severe at times that he was unable to sign his name.

In October 1998, he was found to be hypertensive, with blood pressures as high as 240/140. His liver biochemical tests were abnormal, with elevated transaminases (aspartate aminotransferase (AST): 320 IU/L, alanine aminotransferase (ALT ): 125 IU/L), and gamma glutamyl transferase (GGT) levels (456 IU/L). He was also found to have elevated serum iron and ferritin levels (325 μg/dL and 1400 ng/mL, respectively). A presumptive diagnosis of hemochromatosis was made, and the patient was started on a phlebotomy regime. At this time, he also developed a diffuse, intensely erythematous rash. After undergoing a total of 20 phlebotomies over a period of 9 months, the patient's serum iron and total iron binding capacity (TIBC) were 90 and 385 μg/dL respectively, and his ferritin 963 ng/mL. In the interim, the rash had cleared, leaving deep scars and pigmentation over his back and shoulders. He did not recall a blistering phase of the rash.

In December 1999, his direct and total serum bilirubin concentrations were 0.67 and 2.05 mg/dL, his albumin concentration 4.7 g/dL, the AST and ALT 91 and 45 IU/L respectively, the alkaline phosphatase 145 IU/L and the GGT 833 IU/L. His hemoglobin was 16.3 g/dL, hematocrit 48.9%, mean corpuscular volume 103 fl, white blood count 12,000/μL, and platelets 152,000/μL. Although genetic testing was negative for both the C282Y and H63D hemochromatosis mutations, phlebotomies were continued. He experienced worsening insomnia, mood swings, and increasing difficulty with interpersonal relationships. He also had at least one brief black-out spell, and several episodes of hallucinations. He developed a resting tachycardia of 120 beats per minute, and an echocardiogram was said to show cardiomegaly. His abdominal pain, which was initially primarily mid-epigastric, became more diffuse, and he alternately experienced burning pains as well as tingling paresthesias in his distal lower extremities.

Based on a constellation of symptoms that included tachycardia, abdominal and extremity pain, and an evolving personality disorder, a diagnosis of porphyria was considered. An initial screening panel of urine porphyrins and porphyrin precursors, obtained during a bout of especially severe abdominal pain, revealed an elevated coproporphyrin level, with normal values for δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). A diagnosis of hereditary coproporphyria was made on the basis of the clinical and laboratory findings. He was also diagnosed as being clinically depressed, and briefly underwent psychiatric treatment, although he very quickly discontinued the prescribed antidepressants.

In February 2000, his hepatic biochemical tests had improved further. The direct and total bilirubin were 0.29 and 0.72 mg/dL, respectively; the AST and ALT 70 and 32 IU/L; the albumin 4.1g/dL and the international normalized ratio (INR) 1.07. However, his abdominal pain and neuropsychiatric symptoms had worsened. A liver biopsy revealed no porphyrin crystals, but did show marked steatosis, Mallory hyaline, and bridging fibrosis. The patient denied alcoholism, and was supported in this by family members and co-workers. He was taking no medications at the time of the biopsy, so that the histologic findings could not be attributed to drugs.

On examination at the Mount Sinai Medical Center in May 2000, the patient was noted to be of heavy build, with slightly coarsened facial features. His skin was thickened, with areas of dense scarring, but no erythema, bullae or hypertrichosis were observed. The skin changes were most marked over the trunk, sparing the extremities. Vital signs included a normal temperature, a resting pulse of 120 bpm, and a blood pressure of 140/88 mm Hg. The head, ears, eyes, nose and throat were unremarkable; there was no icterus. Cardiovascular examination suggested a hyperdynamic circulation, but the heart was not enlarged, and no murmurs were appreciated. Abdominal examination was remarkable for massive hepatomegaly and a barely palpable spleen tip. The patient appeared intellectually intact, and neurological testing demonstrated no deficits.

Laboratory investigations showed a hemoglobin of 16g/dL, hematocrit of 48%, mean corpuscular volume of 103 fl, and normal white cell and platelet counts. The serum iron/ TIBC were 90 and 271 μg/dL, respectively (33% saturation), and the ferritin was elevated at 963ng/mL, despite the multiple phlebotomies. His albumin was 4.7g /dL, AST and ALT 204 and 46 IU/L, GGT 1195 IU/L, alkaline phosphatase 288 IU/L and total bilirubin 0.6mg/dL. The INR was 1.18. Serological markers for viral and autoimmune hepatitis were negative. Chest x-ray demonstrated a normal cardiac silhouette. CT scan of the abdomen showed a diffusely heterogeneous and markedly enlarged liver (27 cm in length). The spleen was not enlarged, and there were no varices. Upper gastrointestinal endoscopy demonstrated severe gastritis. A 24-hour urine collection contained ALA levels of 1.7 mg/L (normal), PBG levels of 0.7 mg/L (normal), and total porphyrins of 647 mmol/L (normal up to 300) of which the greatest increase (85%) was in the coproporphyrins.

The liver biopsy was reviewed by the Mount Sinai Department of Pathology.

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