PORPHYRIA

Porphyra (purple)

Porphyria comes from the Latin word for purple, because Porphyria sometimes changes the urine to a deep purple color. The porphyrias are all incredibly rare genetic disorders. There’s 8 in total, but we only have to know the 2 most common. The pathophysiology underlying Porphyria is broken protoporphyrin synthesis. Protoporphyrins help build red blood cells. When an enzyme goes defunct, it leads to a build up of intermediate molecules (which are collectively called porphyrins). These are large and weird molecules. And when they accumulate, weird things happen. Fun fact, porphyrins give blood its red color. You might think that porphyria would cause anemia (as in the case of Sideroblastic Anemia), but that is not the case because the enzymes retain enough functionality to still make RBCs. The problem here is with the accumulation of half-finished porphyrins. Collectively, the 8 different Porphyrias can be diagnosed with an elevated level of Porphyrins in the blood or urine. 

Porphyria Cutanea Tarda

The most common type of porphyria. Deficiency of UROD (Uroporphyrinogen Decarboxylase). Uroporphyrinogen III accumulates, and turns into the more stable Uroporphyrin. Uroporphyrin spills into the blood and urine, and is transported to the skin. When sunlight hits, the Uroporphyrin gets angry and the patient develops blisters. In addition, their AST/ALT rise (because 20% of heme synthesis is in the liver) and their urine turns tea-colored (because Uroporphyrins are in the pee). The genetic mutation is randomly (sporadically) acquired, and although the MOA isn’t fully sussed out, excess iron seems to play a role. And in fact, phlebotomy is one of the treatments. If you remember that heme is partly synthesized in the liver, it’s easy to remember the conditions that make PCT get worse: alcohol and Hep C. To diagnose, look for an elevated Uroporphyrin. For reasons unknown, Hydroxychloroquine may also be used for treatment.  The vampire disease! They get blisters when they go into the sun, and they get better when they drink blood (heme inhibits porphyrin synthesis). 

Acute Intermittent Porphyria 

The most serious type of porphyria. Quite easy to spot on a test: it’s the only cause of intermittent abdominal pain, confusion and colored urine. Autosomal dominant condition (“Mad” King George III might have had it). Deficiency of Porphobilinogen Deaminase (PBGD), which turns Porphobilinogen to Hydroxymethylbilane. Low penetrance and variable symptoms. Symptoms occur as flare ups, whenever Porphobilinogen levels rise. Levels rise when you induce CYP450, with etoh/tobacco and with starvation (hypoglycemia activates ALAS). Porphobilinogen (and ALA) is a neurotoxin. The abdominal pain can mimic appendicitis, and they’ll often undergo several unsuccessful exploratory laparotomies. Their urine is initially clear, when put in the sun it turns purple (see image)! Diagnose by ordering a special blood test looking for elevated Porphobilinogen. The test is only positive during acute attacks. The strategy with treatment is to block heme production using Hemin (a synthetic heme) or glucose (which suppresses ALAS).