Iron Disorders, Porphyria, and HLH Flashcards
Where is the majority of iron stored in the body (2 places)
RBCs and Bone marrow
How much (%) of total iron body content does circulating iron bound to transferrin represent?
0.1%
Describe the effect of Hepcidin on iron absorption
Ferroportin takes iron from the cell into blood stream. Hepcidin downregulates the effect of ferroportin. Hepcidin is itself regulated by total body iron and inflammation (both of which upregulate hepcidin, decreasing the amount of iron in bloodstream)
What mutation is seen in Iron Refractory IDA?
TMPRSS6
What two things help with the absorption of oral iron salts?
Take with Vitamin C or water
Avoid food or coffee
What IV iron formulation requires a test dose?
Iron dextran (for hypersensitivty/anaphylaxis)
Patient with Hgb 10, MCV 56, RDW 19%, Ferritin is 9. Diagnosed with IDA. Given 3 months of oral iron with no improvement, standard IV iron also no improvement. Diagnosis and potential treatment?
IRIDA. High doses of IV iron may overcome this
Pathophysiology of IRIDA
Autosomal recessive TMPRSS6 mutation upregulates hepcidin, meaning there is poor oral iron absorption
Pathogenesis of anemia of chronic inflammation
IL-6 causes increased hepcidin production to minimize iron availability
What test can be more helpful in confirming a diagnosis of anemia of chronic inflammation?
Soluble transferrin receptor, which is less susceptible to changes in inflammation
Pathophysiology of iron accumulation
Iron stores increase and eventually exceed the capacity of transferrin. Then non-transferrin bound iron will accumulate in organs, generating free radicals and ROS, which damage membrane lipids and cells
Three main organ systems affected by iron overload
Liver
Heart
Endocrine (hypogonadism, hypothyroid, Diabetes)
What is a normal liver iron content on MRI liver?
<1.8 mg Fe/g dry weight
What is a normal cardiac T2* when looking at iron content?
> 20 ms
When treating iron overload with phlebotomy, what is the goal ferritin
<100
Cardiac MRI or Liver MRI indications for chelation
LIC >3 or 7 mg/g dry weight
T2* <20 ms
Treatment goals (ferritin, liver MRI, cardiac MRI) for chelation therapy
Ferritin <1000
LIC 2-7 mg/g
Cardiac T2* >20 ms
Usual first line iron chelator
Deferasirox
Adverse effects of deferasirox
High frequency hearing loss
GI discomfort
Renal toxicity
What is the preferred iron chelator for patients with cardiac iron overload and dysrhythmias?
Deferoxamine
Adverse effects of deferoxamine
Local reactions
High frequency hearing loss
Vision loss, color vision changes, retinal changes
bony deformities
Infection with Yersinia and Klebsiella
What is the iron chelator that has a risk of agranulocytosis
Deferiprone
How do you treat a pregnant woman with Hereditary hemochromatosis?
Weekly IVIG starting at 18 weeks
Pathophysiology of Hereditary Hemochromatosis
AR mutation in HFE gene (most commonly, but can see mutations in transferrin receptor, ferroportin. These mutations downregulate hepcidin, meaning an increased absorption of iron (4x)
What is the pathophysiology of inherited sideroblastic anemia?
X-linked mutation in ALAS2 is most common. That leads to pathologic iron accumulation in mitochondria of erythroid precursors. These iron-laden mitochondria encircle the nucleus and are called ringed sideroblasts
Peripheral smear findings of someone with siderobalstic anemia
Dimorphic population of RBCs
Hypochromic, microcytic cells
Prussian blue staining shows ringed sideroblasts and Pappenheimer bodies
Treatment for sideroblastic anemia
Pyridoxing (B6) supplementation
Pathophysiology of Porphyria Cutanea Tarda
UROD mutation causing deficiency of Uroporphyrinogen decarboxylase
Clinical features of porhyria cutanea tarda
Blistering skin lesions on sun exposed areas, susceptibility increased by alcohol, smoking, estrogen, HCV, HIV.
Lab diagnosis of PCT
Plasma or urine porphyrins are elevated
ALA and PBG are normal
Treatment and treatment goal for PCT
Phlebotomy for target ferritin <20
Low dose HCQ also an option
Treat underlying HCV if present
Long term complications of PCT
Skin infection, scarring
Liver damage, HCC
Pathophysiology of Acute Intermittent Porphyria
Autosomal dominant mutation causing deficiency in porphobilinogen deaminase, leading to elevation of porphobilinogen and Aminolevulinic acid (ALA)
Clinical manifestations of AIP
Neurologic symptoms
Abdominal pain
No skin symptoms
Dark urine
How to make laboratory diagnosis of AIP
Urine prophobilinogen will be markedly elevated
ALA will also be high
Management for acute AIP attacks?
Hemin
Can do glucose for mild attaks
What is the treatment to prevent AIP attacks?
Givosiran
What is the indication of Givosiran?
Prevention of acute intermittent porphyria attacks
Pathophysiology of Erythropoietic Protoporphyria?
AR loss of function mutation in ferrochelatase
Clinical manifestation of Erythropoietic Protoporphyria
Painful, non-blistering photosensitivity
Management of Erythropoietic Protoporphyria
Afamelanotide and beta-carotene can darken skin, but doesn’t change porphyrin levels
BMT can be curative
8 Diagnostic Criteria for HLH (and how many do you need to make the diagnosis?)
5 of 8
Fever
Splenomegaly
Cytopenia
HyperTG and/or hypofibrinogenemia
Ferritin >500
sCD25 >2400
Decreased or absent NK-cell activity (not useful in adults)
Hemophagocytosis in bone marrow, CSF, or LNs
What is the leading organism causing acquired HLH?
EBV
What is the use of the Optimized HLH inflammatory index?
Predictive of mortality. Suggests that the inflammatory profile (high sCD25 and ferritin) are the most important things for prognosis
Treatment for HLH
Dexamethasone, cyclosporine, and etoposide
What are treatment options for someone relapsed with HLH after prior induction therapy?
Alemtuzumab
First Line Treatment for Post-Immune Effector Cell Hyperinflammatory syndromes
Anakinra +/- steroids
Second Line Treatment for Post-Immune Effector Cell Hyperinflammatory syndromes
Ruxolitinib
Third line treatment for Post-Immune Effector Cell Hyperinflammatory syndromes
Low dose etoposide
