Acute intermittent porphyria (AIP) is characterized by attacks of abdominal pain and neuropsychiatric symptoms. In northern Sweden, about half of those patients carrying the gene encoding for this condition have experienced attacks with abdominal pain, more frequently and more severely affecting women.
In biochemical terms, AIP is an autosomal hereditary metabolic aberration resulting from a partial defect in the activity of the third-step enzyme (porphobilinogen deaminase [PBGD]) during the course of heme synthesis (1). Carbohydrate ingestion blocks d-aminolevulinic acid (ALA)-synthase, as has been demonstrated in numerous clinical and experimental studies. However, the mechanisms by which carbohydrates modulate the components of porphyrins and heme synthesis are highly complex and only partially elucidated to date (2).
The main long-term complications of AIP are polyneuropathy (3), hepatocellular carcinoma (HCC) (4), and renal insufficiency (5). Treatment of AIP patients entails treating both the symptoms and the complications, but also requires an endeavor to reverse the fundamental disease by prescribing a carbohydrate-rich diet and by treating the attacks with intravenous infusions of glucose (2) or heme (6).
We conducted a population-based study on AIP patients aged ≥18 years living in northern Sweden, in which 319 participated (95%). A total of 16 patients (5 women) with AIP and type 2 diabetes were found, with a mean age of 67 years. Eight of these patients had AIP symptoms, with three patients suffering severe, recurring attacks. After the onset of their diabetes, no patient suffered attacks or any other AIP symptoms (7).
During several weeks in the hospital ward, it was possible to closely examine and study the course of developing diabetes in a 52-year-old woman who had previously been hospitalized at the Department of Medicine due to AIP attacks on 46 occasions. At 4 years after menopause, her AIP was still unremitting, with recurrent attacks. However, after she had developed a metabolically rather mild type 2 diabetes, the AIP symptoms subsided. Mean values on 13 occasions of testing for urinary porphobilinogen (PBG) during 6 months before and on 11 occasions during the first 4 months after she developed diabetes were 65.9 and 10.2 μmol/l, respectively (reference levels 1.3–11.0 μmol/l) (P = 0.0001). Now, 5 years later, she is still free from AIP symptoms, the levels of ALA and PBG in her urine fluctuate around normal or just above the upper reference levels, and she leads “a good life.”
More than 2 decades ago on the hospital ward, I noticed two patients, both with AIP and HCC, which are rare diseases in the Western world. To test whether this was a random finding, a retrospective study of HCC in deceased AIP patients was performed using records of 206 carriers >15 years of age. The diagnosis was based on a clearly depressed activity of PBGD. Statistically, only 1 patient with HCC was expected, yet 11 (7 women) were found. This coincidence was highly significant. The findings were verified in the autopsy records. The mean age was 67 years (8).
Two municipalities in northern Sweden, Arjeplog (population 3,800) and Arvidsjaur (population 8,080), have the highest prevalence of AIP patients in the world (1–2%). In a retrospective population-based study of mortality during the period 1978–1990, AIP patients (n = 33) were compared with all other individuals who had died during this period (n = 2,089). In the AIP group, nine patients (27%) had HCC, whereas in the other group, only four patients (0.2%) had HCC (<0.0001) (9).
In an attempt to elucidate the molecular mechanism of the carcinogenesis in this HCC, archived specimens were collected (9). Selective mutations at codons 249 and 166 of the p53 gene have been described in HCC, associated with aflatoxin and hepatitis B virus (10). HCC in AIP, on the other hand, is characterized by an absence of the genes mentioned and by only mild or no liver cirrhosis. A diminished free heme pool and an increased concentration of ALA could lead to an increase in reactive oxygen radicals and may, in a longer perspective, cause cancer (11).
Recurrant AIP attacks ceased when the patients became diabetic. None of the 16 diabetic patients with AIP had HCC. Of all the 30 AIP patients with HCC registered, none had diabetes, whereas in a population-based group of individuals in southern Sweden (mean age 67 years), diabetes was found in 12.8% of the men and 15.0% of the women (12). This suggests that diabetes also counteracts HCC in AIP patients, probably by normalization of ALA (11).
Address correspondence to Dr. Folke Lithner, Department of Internal Medicine, University Hospital, Umea, Sweden S-90185. E-mail:.
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