Heme synthesis disorders: Pathology review

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Case Study0:00–0:58

18 year old Christopher is brought to the emergency room by his best friend Paul after suddenly getting abdominal cramps at a party.
Cristopher goes to the restroom while you ask Paul a few questions. Paul tells you that Cristopher was behaving strangely at the party, and adds that it was his first time drinking alcohol.
When Christopher comes back from the restroom, he tells you that his urine had a reddish color. Unfortunately, his family history is unknown, since he was adopted at a very young age.
Next to him, there’s 45 year old Magdalene, who developed skin blisters on her hands and forearms after spending the day having some alcoholic cocktails on the beach.
Upon further questioning, Magdalene mentions that her urine had a strange tea color earlier. You decide to take a look at her past medical history, which reveals that Magdalene had hepatitis C a few weeks ago.

Physiology0:58–3:23

Based on the initial presentation, both Christopher and Magdalene seem to have some form of heme synthesis disorder. Heme synthesis disorders are associated with hereditary or acquired deficiencies of enzymes that are involved in the heme synthesis pathway.
But first let’s go over the heme synthesis pathway really quick! It’s important to remember that heme synthesis occurs in the liver, where heme is used in the cytochrome P450 enzyme system, as well as in the bone marrow where heme is used to synthesize hemoglobin.
Now, heme synthesis begins in the mitochondria, where succinyl CoA binds to glycine via aminolevulinic acid or ALA synthase to produce aminolevulinic acid or ALA.
Remember, this is the rate-limiting step for heme synthesis, meaning that it’s the slowest step in the pathway, and it requires vitamin B6, or pyridoxine, as a cofactor.
What’s also high yield is that this step is stimulated by low levels of heme, while it’s inhibited by elevated levels of heme, as well as glucose and hemin, which is an oxidized form of heme that contains ferric iron or Fe3+ with chloride.
Okay, then, ALA is transported to the cytosol, where it gets converted to porphobilinogen or PBG via aminolevulinic acid or ALA dehydratase, which is a zinc-containing enzyme.
From there, four molecules of porphobilinogen come together to form hydroxymethylbilane with the help of porphobilinogen deaminase.
Note that porphobilinogen deaminase is sometimes called uroporphyrinogen I synthase or hydroxymethylbilane synthase, or HMBS for short.
Afterwards, hydroxymethylbilane is converted via uroporphyrinogen III cosynthase to uroporphyrinogen III, which is then turned to coproporphyrinogen III via uroporphyrinogen decarboxylase Next, coproporphyrinogen III is brought back into the mitochondria and converted into protoporphyrinogen IX, which is then converted to protoporphyrin IX.
Lastly, the enzyme ferrochelatase adds an iron molecule to protoporphyrin IX, and we’ve got ourselves a complete molecule of heme!
Alright, now, for your exams, the most high yield causes of heme synthesis disorders are sideroblastic anemia, lead poisoning, acute intermittent porphyria, and porphyria cutanea tarda.Starting with sideroblastic anemia, which can be genetic or acquired.

Pathology3:23–3:37

The most common genetic cause is an X-linked mutation in the gene coding for ALA synthase. On the other hand, the most important acquired cause is vitamin B6 or pyridoxine deficiency.

Sideroblastic anemia3:37–6:01

For your exams, remember that this can result from inadequate dietary intake, chronic alcohol abuse, and treatment with isoniazid.
In any case, heme synthesis is impaired, so there’s an excess of iron that’s not being used and ends up accumulating throughout the body, particularly in the heart, liver, spleen, kidneys, and the intestines.
As a result, individuals with sideroblastic anemia may develop cardiomyopathy, cirrhosis, enlarged spleen, kidney failure, and diarrhea.
Diagnosis of sideroblastic anemia relies on blood tests showing microcytic and hypochromic red blood cells, meaning that they are smaller and paler than normal, which indicates that they contain low quantities of hemoglobin.
In addition, blood tests will reveal high iron and high ferritin, which stores iron, as well as a high saturation of transferrin, which is a molecule that transports iron in the blood, and normal or low total iron binding capacity or TIBC, which indicates the amount of unbound transferrin in the blood.
In a peripheral blood smear, what we expect to see is red blood cells with basophilic stippling, which refers to tiny blue or purple granules of ribosomal RNA that are dispersed throughout the cytoplasm.
And that’s a high yield fact! Additionally, pappenheimer bodies or cytoplasmic granules of iron may also be observed inside the red blood cells.
Finally, upon a bone marrow biopsy, a Prussian blue stain can show the iron-laden mitochondria forming a ring around the nucleus, producing the classic ringed sideroblast appearance.All right, now treatment of sideroblastic anemia involves managing iron overload with therapeutic phlebotomy or bloodletting, as well as deferoxamine, an iron chelating agent.
In addition, pyridoxine supplementation can also be useful. Finally, severe cases may require a bone marrow or liver transplant.
Now, another cause of acquired sideroblastic anemia is lead poisoning. However, what’s important for you to know is that lead inhibits both ALA dehydratase and ferrochelatase.
As a result, there’s build up of ALA and protoporphyrin IX in the blood. Now, remember that lead poisoning usually occurs in children ingesting lead-containing paint chips, as well as adults who inhale lead while working in mines, or those who are frequently in contact with batteries or bullets.

Lead poisoning6:01–7:26

High yield symptoms of lead poisoning include abdominal pain, headaches, memory loss, and constipation. Lead can also accumulate and form lead lines on the metaphysis of long bones.
Other telltale signs include Burton lines, which are blue lead lines that can appear at the gingiva. Finally, some individuals may present with wrist and foot drop due to demyelination of peripheral nerves causing peripheral neuropathy, Now, for diagnosis of lead poisoning, blood tests would obviously show high lead levels, in addition to the sideroblastic anemia.
Finally, X-rays might also be done to look for lead lines on long bones. The main treatment for lead poisoning consists of chelating agents like succimer for children and dimercaprol or EDTA for adults.
Next up is acute intermittent porphyria, which is caused by an autosomal dominant mutation of the HMBS gene, coding for porphobilinogen deaminase.
However, keep in mind that the mutation alone is usually not enough to develop any symptoms. Instead, there must be a trigger like alcohol consumption, starvation, and medications that induce or activate cytochrome P450, such as phenobarbital, griseofulvin, and phenytoin.

Acute intermittent porphyria7:26–9:02

Normally, these triggers would promote the synthesis of heme in the liver by stimulating ALA synthase. However, with acute intermittent porphyria, the heme synthesis pathway stops at the defective porphobilinogen deaminase, which can’t convert porphobilinogen to hydroxymethylbilane.
As a result, both porphobilinogen and its precursor aminolevulinic acid or ALA build up in the blood.Once triggered, acute intermittent porphyria present as acute attacks of symptoms, which can be remembered as the 4P’s for Painful Abdomen, Polyneuropathy, Psychological disturbances, like disorientation and anxiety, and Port-wine colored urine, caused by the excess porphobilinogen that ends up being excreted in the urine.
That’s because when porphobilinogen is exposed to sunlight and oxygen, it gets oxidized and turns to a reddish, wine color.
Treatment of acute intermittent porphyria includes analgesics to relieve abdominal pain, and ALA synthase inhibitors, such as glucose and hemin.
Finally, let’s discuss porphyria cutanea tarda, which is the most common type of porphyria. Now, porphyria cutanea tarda is caused by uroporphyrinogen decarboxylase deficiency that can be genetic, or most often acquired, which is usually due to hepatitis C infection.
A high yield similarity with acute intermittent porphyria is that symptoms of porphyria cutanea tarda can be triggered by alcohol consumption, as well as sunlight exposure, and having an excess of iron in the blood for any reason.

Porphyria cutanea tarda9:02–11:05

However, in a test question, keep in mind that unlike acute intermittent porphyria, porphyria cutanea tarda is not triggered by medications that induce cytochrome P450.
In any case, uroporphyrinogen III can’t be converted to coproporphyrinogen III. Now, the excess uroporphyrinogen ends up being excreted in the urine, and when exposed to sunlight, it becomes oxidized to uroporphyrin.
This gives the urine a tea or sometimes red color, which can look similar to acute intermittent porphyria. But what helps set these two apart is that the excess uroporphyrinogen can also accumulate in the skin, so porphyria cutanea tarda also presents with photosensitivity.
So, when these individuals are exposed to sunlight, they can develop hyperpigmentation or darkening of the skin, as well as skin blisters, which usually appear on their hands and forearms.
At the same time, heme synthesis stops, so the un-used iron can build up in the liver, leading to cirrhosis or liver damage.
Treatment of porphyria cutanea tarda includes avoiding triggers, such as sunlight exposure. Furthermore, individuals who have high levels of iron in the blood can be managed via phlebotomy.
Finally, antimalarials, such as hydroxychloroquine, can also be used to help remove the excess iron from the liver and promote its excretion into the urine.
All right, as a quick recap… Heme synthesis disorders are caused by genetic or acquired defects in enzymes involved in the heme synthesis pathway and they include sideroblastic anemia, lead poisoning, acute intermittent porphyria, and porphyria cutanea tarda.
Causes of sideroblastic anemia can be genetic, such as an X linked mutation in the ALA synthase gene, or acquired, due to vitamin B6 deficiency, most often caused by isoniazid.
Symptoms are due to organ damage by the excess iron. Lead poisoning can occur in children ingesting lead-containing paint chips, and adults who inhale lead while working in mines, or are frequently in contact with batteries or bullets.

Review11:05–13:11

Lead inhibits ALA dehydratase and ferrochelatase, resulting in ALA and protoporphyrin IX build up in the blood. Lead poisoning can present with sideroblastic anemia, abdominal pain, headaches and memory loss, lead lines on the metaphysis of long bones, Burton lines at the gingiva, and wrist and foot drop.
Acute intermittent porphyria is caused by an autosomal dominant mutation of the gene that encodes for porphobilinogen deaminase, resulting in the build up of porphobilinogen and ALA.
Acute attacks are triggered by alcohol, starvation, and CYP450 inducers. Symptoms of attacks include painful abdomen, polyneuropathy, psychological disturbances, and port-wine colored urine.
Treatment includes analgesics, glucose and hemin. Finally, porphyria cutanea tarda is characterized by deficiency of uroporphyrinogen decarboxylase, which can be genetic or acquired due to hepatitis C infection.
Symptoms can be triggered by alcohol consumption or sunlight exposure, and include photosensitivity, hyperpigmentation, blistering, and tea-colored urine.
Treatment includes avoiding sunlight exposure, as well as phlebotomy and antimalarials. Going back to our cases, Christopher is the 18 year old male who suddenly developed a painful abdomen and psychological disturbances while drinking alcohol at a party.
These are 2 of the 4P’s characteristic of an attack of acute intermittent porphyria, and alcohol is one of the main triggers.
The final clue is that Christopher’s urine had a reddish or port-wine color, which is also one of the 4P’s. All this points to acute intermittent porphyria which is an autosomal dominant condition, but the fact that he’s adopted made him unaware of his condition until this party, where he was drinking alcohol for the first time.

Summary13:11–14:19

Cristopher was treated with analgesics, along with glucose or hemin. On the other hand, Magdalene is the 45 year old who developed skin blisters on her hands and forearms, as well as tea-colored urine after spending the day at the beach.
This, along with her history of hepatitis C infection, should make you think of porphyria cutanea tarda, which was triggered by sunlight exposure combined with alcohol consumption, so Magdalene was instructed to avoid these triggers.
color, which is also one of the four pees, all this points to acute intermittent porphyria, which is an autosomal dominant condition, the fact that he's adopted made him unaware of his condition until this party where he was drinking alcohol.
For the first time, Christopher was treated with analgesics along with either glucose or human. On the other hand, Magdalene is the 45 year old who develop skin blisters on her hands and forearms, as well as tea colored urine, after spending the day at the beach.
This along with their history of hepatitis C infection, should make you think of porphyria cutanea tarda, which was triggered by sunlight exposure combined, with alcohol consumption.
So that the land was instructed to