'Madness' of King George III: Link Between Fasting And Acute Attacks Of Porphyria

Porphyria disease is caused by defects in the enzyme pathwaythat produces heme, a critical iron compound found throughout the body,most notably in red blood cells. The defects lead to the overproductionand toxic accumulation of the intermediate molecules that eventuallybecome heme. Researchers and physicians have long known that fastingcan cause acute attacks of the disease, and that the attacks can berelieved with glucose or other high-carbohydrate treatments, but theexact link between fasting and the attacks has been mysterious untilnow.

In the Cell study, Bruce Spiegelman of the Dana-Farber CancerInstitute and Harvard Medical School and colleagues show that fastingincreases levels of a metabolic protein called PGC-1a. The "starvation"signal that fasting sends throughout the body prompts PGC-1a tojump-start the process of creating glucose from scratch in the liver.However, PGC-1a also regulates the activity of an enzyme called ALAS-1,the first key enzyme in the heme production pathway.

The higher levels of PGC-1a produce higher levels of ALAS-1,leading to a toxic buildup of precursor heme molecules, Spiegelman andcolleagues found.

The finding explains why glucose infusions are helpful intreating acute attacks since the glucose boost can shut off thestarvation signal and return PGC-1a levels back to normal.

However, the discovery could pave the way for new porphyriatherapies that focus on PGC-1a itself rather that relying onhigh-carbohydrate treatments, the researchers suggest.

"Unfortunately, because of the therapeutic high carbohydrateintake, patients with hepatic porphyrias are prone to weight gain.Losing excess weight is very difficult for some of these patientsbecause of fasting-induced acute attacks. Hopefully, our findingsdescribed here might lead to the development of more specifictreatments for these patients," Spiegelman and colleagues say.

However, since fasting boosts PGC-1a levels, "it is also important that patients not fast or strongly diet," Spiegelman adds.

The researchers tested the link between PGC-1a and ALAS-1 inmice engineered to lack PGC-1a in the liver. In these mice, ALAS-1levels did not rise as dramatically as in normal mice after fasting orafter chemical treatment that mimicked some of the enzyme defects ingenetic porphyria.

Although drugs like alcohol and barbiturates can also provokean acute porphyria attack, PGC-1a is not involved in attacks brought onby barbiturates, Spiegelman and colleagues found after examining theeffects of phenobarbital in both normal mice and mice without PGC-1a intheir livers.

Acute porphyria attacks can include severe abdominal pain, skinsensitivity to sunlight, and psychiatric disorders like hysteria, whichmay have been the source of King George III's well-known insanity,according to some historians.

The other members of the Spiegelman research team include ChristophHandschin, Jiandie Lin, James Rhee, Sherry Chin, Pei-Hsuan Wu, andAnne-Kathrin Peyer and Urs Meyer of the University of Basel in Basel,Switzerland. The study was supported by the National Institutes ofHealth and the Swiss National Science Foundation.

Handschin et al.: "Nutritional Regulation of Hepatic HemeBiosynthesis and Porphyria through PGC-1a" Publishing in Cell, Vol.122, pages 505-515, August 26,2005, DOI 10.1016/j.cell.2005.06.040. www.cell.com