Key points to remember about sideroblastic anemia for the USMLE

-Sideroblastic anemia results from hereditary (X-linked) or acquired disorder of heme synthesis.

-It is a microcytic hypochromic anemia with a high RDW (red cell distribution width) Same as iron deficiency anemia.

-Iron studies will distinguish the two. In sideroblastic anemia serum iron, serum ferritin and transferrin saturation are increased.

-The impaired synthesis of heme leads to retention of iron in the mitochondria. The nucleated RBC's show aggregation of iron in the mitochondria and has a perinuclear distribution. These cells are called ringed sideroblasts, which are characteristically seen in sideroblastic anemia.

-Severity can be mild or severe enough to need frequent transfusions.

-Treatment: Pyridoxine helps in some rare inherited cases but manu need periodic transfusions. Stem cell transplantation has been used to treat children who are dependent on blood transfusion.

Hemolytic-uremic syndrome

Hemolytic-uremic syndrome (HUS), is essentially a vasculopathy characterized by hemolytic anemia, acute renal failure and thrombocytopenia. It is caused by a variety of agents but most commonly by E. coli O157:H7, which is a gram negative bacteria acquired via contaminated food or drinks.

Pathophysiology:
-Shiga toxin-producing E. coli (STEC) or enterohemorrhagic E. coli (EHEC) produce a toxin called verotoxin or shiga-like toxin.
-Toxin enters the bloodstream and causes damage to the body's vascular endothelium.
-Endothelial damage leads to platelet activation that causes thrombocytopenia. The renal glomerular endothelial cells express a receptor for the toxin.

Clinical features:
-HUS is characterized by the triad of hemolytic anemia, thrombocytopenia, and acute renal failure.
-Preceding bloody diarrhea may or may not be present.
(HUS must be distinguished from Thrombotic thrombocytopenic purpura (TTP) which in addition to the triad above has fever and neurological signs. TTP is caused by an acquired defect in the protein ADAMTS13.)

Treatment:
-Supportive treatment for low platelets (transfusion if bleeding)
-Supportive treatment of renal failure (electrolyte balance, dialysis as needed)
-Plasmapheresis is often used in early cases to get rid of the circulating toxin
-With supportive care majority of the patients have good renal outcomes

Pemphigus

Pemphigus is an autoimmune disorder of the skin and mucous membranes characterized by blisters associated with the binding of IgG autoantibodies to epithelial cell surface. The common form is called Pemphigus vulgaris. Antigens in pemphigus are believed to be desmoglein 1 and desmoglein 3. Antibodies belong to IgG1 and IgG4 type.

Mean age of onset is approximately 50-60 years. Histologic changes consist of intercellular edema with loss of intercellular attachments in the basal layer. Suprabasal epidermal cells separate from the basal cells to form clefts and blisters. These findings can help differentiate phemphigus vulgaris from pemphigus foliaceous, which demonstrates a more superficial epidermal cleavage.

Primary Amyloidosis- Types, proteins and clinical associations

Type	Deposited Protein	Clinical Associations
Systemic	Immunoglobulin lambda chains	Multiple myeloma
	Transthyretin	Familial amyloidosis, senile cardiac amyloidosis
	Amyloidosis – A protein	Inflammation-associated amyloidosis
	Beta2 -microglobulin	Dialysis-related amyloidosis
	Immunoglobulin heavy chains	Systemic amyloidosis
Hereditary	Fibrinogen alpha chain, Apo A1 and Apo A2	Familial systemic amyloidosis
	Lysozyme	Familial systemic amyloidosis
Central nervous system	Beta protein precursor	Alzheimer's
	Prion protein	Creutzfeldt-Jakob disease, Gerstmann-Strãussler-Scheinker disease, fatal familial insomnia
	Cystatin C	hereditary cerebral hemorrhage with amyloidosis (Icelandic)
Ocular	Gelsolin	Familial amyloidosis (Finnish)
	Lactoferrin	Familial corneal amyloidosis
	Keratoepithelin	Familial corneal dystrophies
Localized	Calcitonin	Thyroid Carcinoma (Medullary)
	Amylin	Insulinoma, type 2 diabetes
	Atrial natriuretic factor amyloid	Isolated atrial amyloidosis
	Prolactin	Pituitary amyloid
	Keratin	Cutaneous amyloidosis
	Medin	Aortic amyloidosis in elderly people

Novel Risk Factors for Atherosclerosis (CRP, Lipoprotein-a, Fibrinogen and Homocysteine)

CRP- C-reactive protein: High CRP reflects inflammation, and has been shown to correlate with the occurrence of myocardial infarction and peripheral arterial disease. 

Homocysteine levels: It is a well known fact that homozygous hyperhomocystinemia is associated with early atherosclerosis and stroke. However, approximately 5-7% of the general population have mild elevations of plasma homocysteine, and recent research have focussed on refuting or establishing if this population is at a higher risk for cardiovascular events. A number of treatments have been postulated for those with high homocysteine levels including folic acid and pantothenic acid. 

Fibrinogen: In recent studies high levels of fibrinogen have been found to be strongly related to cardiovascular events in apparently healthy individuals.

Lipoprotein-A: Lipoprotein A is an LDL like substance in the blood that remains bound to apolipoprotein A. It may promote atherosclerosis by its ability to be oxidized. Some studies have shown that Vitamin B3 (Niacin) can decrease its levels but the clinical significance is still unclear.

Enteropeptidase

Enteropeptidase is a pancreatic enzyme needed for the conversion of Trypsinogen to Trypsin inthe small intestine. Deficiency of this enzyme will lead to diarrhea, growth retardation, hypoalbuminemia and edema due to protein malabsorption.

SCID (Severe Combined Immunodeficiency)

Adenosine Deaminase Deficiency causes accumulation of adenosine in T-lymphocytes causing them to malfunction and lead to of the types of an immunodeficiency condition called SCID (Severe Combined Immunodeficiency).

Cystinuria

Cystinuria – is due to failure of renal tubules to absorb amino acid Cysteine. Cyanide test which detects Sulfhydryl Groups will detect presence of Cystine in the urine.

Osteoblastic and Osteoclastic markers

Bone Specific Alkaline Phosphatase – marker of Osteoblastic Activity

Tartrate Resistant Acid Phosphatase, Hydroxyproline and Deoxypyridinoline – markers of Osteoclastic Activity.

Sydenham's Chorea

Q: In Sydenham's Chorea (post streptococcal infection) what is the histopathology of the brain likely to show?

 

A: Necrotizing arteritis of the caudate, putamen & thalamus