Series of confusing topics for usmle candidate's

I have already declared in my experience part that I will discuss about "100 confusing topics". This is the First one for you-

Surely you may get 4/5 marks more from this topics in the real test because it is very very high yield topics.

Topic 1: Fatty acid catabolism

1. Hypoketotic hypoglycemia with intracellular fatty acyl carnitines on muscle biopsy- it may be LCAD or MCAD deficiency. If question says carnitine is present, that means carnitine can't be deficient, because if it were, then you would only get fatty acyl-CoA derivatives but not anything carnitines related. Therefore, the answer here would be MCAD or LCAD deficiency.

2. Intestinal FA that are 12 or more carbons in length are absorbed in lymph and bypass liver. 12+ carbon FA are termed long chain. So, if the question stem mentions the classic hypoketotic hypoglycemia and then tells you the build up of 16C FA like palmitic acid, than the answer is LCAD deficiency, not MCAD deficiency.

3. Acetyl CoA production is decreased in LCAD, MCAD or SCAD deficiency that causes hypoglycemia. This is because acetyl CoA is a cofactor for pyrovate carboxylase, the first step in gluconeogenesis.

4. For MCAD deficiency, they might give you a scenario that's very similar to McArdle's. Both present as muscle cramping and myoglobinuria. But in MCAD deficiency, these cramping and myoglobinuria present after prolong exercise where they present just immediately after intense exercise in McArdle's(within minutes). So, MCAD deficiency- present after prolong exercise such as hours; McArdle's- present within minutes of exercise. Both have intramuscular clear droplets on muscle biopsy but clear droplet for MCADD is due to stored lipid and clear droplet for McArdle is due to stored glycogen. Pretty Examiner loves to puzzle you by these information. So, be careful. Another point, myalgias significantly improves after brief periods of rest in McArdle that is called second wind phenomenon( may be due to increased blood flow at rest and delivery of free FA to the muscle for energy). This phenomena is absent in MCAD deficiency.

5. Hyperammonemia can occur with MCAD deficiency because decreased acetyl CoA- decreased TCA cycle activity- decreases ATP synthesis- decreased carbamoyl phosphate synthesis- decreased urea cycle activity- increased blood ammonia. Another mechanism of hyperammonemia is that, body try to produce glucose by gluconeogensis through protein breakdown and all we know ammonia comes from breakdown of protein.

6. Short chain FA(2-4 carbons) and medium chain FA(6-12 carbons) diffuse freely into mitochondria to be oxidized. Long chain FA(14-20 carbons) are transported into mitochondria by a carnitine shuttle to be oxidized. VLCFA(>20carbons) enter peroxisomes via an unknown mechanism for oxidation.

7. VLCFA are first become short in peroxisome by acyl CoA oxidase and produce FADH2. It itself oxidize VLCFA with reaction of O2 and produce H2O2 that convert into H2O by catalase. This process produce LCFA from VLCFA.

8. Symptom of Carnitine deficiency is mostly muscle specific because of genetic abnormality. So, you may see only muscle specific symptom(weakness, hypotonia, cardiac muscle problem like cardiomyopathy) with hypoketotic hypoglycemia. But MCAD deficiency has generalized symptomes like vomiting, lethergy, seizures, liver dysfunction, coma etc.

9. Mitochondrial membrane is impermeable to FA due to their negative charge, so carnitine is needed. Carnitine acyl tranferase 1 present in cytosol and 2 present in mitochondria.

10. Although most beta oxidation is mitochondrial, super long FA for beta oxidation and branched chain FA for alpha oxidation occurs in peroxisomes. Refsum and Zellweger syndromes are deficiencies of the peroxisomal system. Chlorophyll should be avoided in the diets of those with Refsum disease because it liberates phytol intestinally which is anabolized to phytanic acid that can not be catabolized because phytanic acid is also a branched chain FA. Also, defect in VLCFA transport across peroxisomal membrane leads to accumulation of VLCFA in blood and tissues reaulting in X linked adrenoleukodystrophy. The most severely affected tissues are the myelin in the CNS, Adrenal cortex and Leydig cells in the testes.

Last information: Why acetyl CoA from FA is needed??

Ans: Acetyl CoA needs TCA cycle to be oxidized. Oxaloacetate as a catalyst performs vital role to support and maintain TCA cycle activity. Glucose is the primary source of OAA. Therefore, through OAA, carbohydrates fuels TCA cycle to continue as a flame in which acetyl CoA, the end product of fat oxidation is finally oxidized(burn out). Moral of the story- - - low carbohydrate intake in programmed body weight loss ultimately fails in maintaining lasting weight loss because the ability to burn stored body fat is blunted due to carbohydrate deficiency since fat oxidation is dependant on the background of carbohydrate catabolism