D-lactic acidosis in short bowel syndrome

Hello everyone!

D-lactic acidosis is an unusual form of lactic acidosis.

Which patients develop D-lactic acidosis?
1. In patients with jejunoileal bypass, small bowel resection, or other causes of the short bowel syndrome.
2. Patient who receives or ingests a large amount of propylene glycol
3. Patients with diabetic ketoacidosis

In this post, I'm going to specifically talk about D-lactic acidosis in patients with small bowel syndrome.

How do patients with D-Lactic acidosis present?

Increased anion gap metabolic acidosis.
Neurologic findings of intermittent confusion, slurred speech, and ataxia.

Why does it happen in patients with small bowel syndrome?

Glucose and other carbohydrates are normally absorbed by the small bowel. If the small bowel is bypassed, removed, or diseased, then delivery of these substances to the colon increases.

Also, overgrowth of gram-positive anaerobes, such as Lactobacilli seen in small bowel syndrome contributes to lactic acidosis.

How is it metabolized?

D-lactate is not metabolized by L-lactate dehydrogenase, the enzyme that catalyzes the conversion of the physiologically occurring L-lactate into pyruvate. Thus, D-lactate is slowly metabolized in humans, accumulates in body fluids, and generates metabolic acidosis.

Diagnosis:
Laboratory studies show increased anion gap metabolic acidosis with normal plasma lactate levels, because the D-isomer is not measured by conventional laboratory assays for lactate. Diagnosis is confirmed by specifically measuring D-lactate.

Treatment:
Sodium bicarbonate if D-lactic acidosis and acidemia are severe.

Oral antimicrobial agents (such as metronidazole, neomycin, or vancomycin) can be used when D-lactic acidosis that decrease the number of D-lactate-producing organisms.
FYI: Although antimicrobials are sometimes helpful, they can occasionally precipitate D-lactic acidosis in susceptible subjects by causing an overgrowth of lactobacilli.

Low-carbohydrate diet (or the use of starch polymers rather than simple sugars) is also helpful because it diminishes carbohydrate delivery to the colon.

That's all!

-IkaN

Protein gap

The gamma gap aka paraprotein gap or protein gap is the difference between total serum proteins and albumin measured from a comprehensive metabolic panel.

Albumin accounts for the majority of total serum protein.

Viral infections, plasma cell malignancies, or autoimmune conditions there is an excess of immunoglobulins, raising the total amount of serum protein independent of albumin.

The gamma gap is typically considered to be elevated if it is above 4 g/dL.

In the right clinical context, gamma gap should be worked up with SPEP, UPEP, and a serum free light chain assay.

Random exercise: Calculate the protein gap.
Total protein 8.9 g/dL (normal 6.4-8.3 g/dL)
Albumin is 3.6 g/dL (normal 3.4-4.8 g/dL)

That's all!

-IkaN

Pathophysiology: Diabetic Ketoacidosis

Hello guys, here’s a whiteboard summary of how DKA happens.

[Please click on the image to enhance it]

- DKA is a medical emergency. It’s a complication of type 1 diabetes.
- DKA has a triad of hyperglycemia, ketosis [metabolic acidosis] and dehydration.
- Main ketone bodies are beta-hydroxybutyrate and acetoacetate. Acetone is only a minor ketoacid.
- Lactic acidosis also contributes to metabolic acidosis.
- More glucose in blood leads to more glucose filtered into urine causing osmotic diuresis.


- Ashish Singh 

Orotic aciduria

Hello Awesomites!
The question has helped me to learn the pyrimidine biosynthesis and urea cycle better. Felt like sharing it.

Let's get started.

OROTIC ACIDURIA= Excessive excretion of orotic acid in urine.

Orotic aciduria is caused by defect in either UMP synthase enzyme or Ornithine trancarbomylase (OTC) enzyme.

When UMP synthase is defective, orotic acid builds up and the synthesis of nucleic acid is impaired, leading to deficient hematopoiesis and growth. Orotic aciduria is associated with megaloblastic anemia due to decreased pyrimidine synthesis. This megaloblastic anemia is refractory to Vitamin B12, folic acid supplementation. This megaloblastic anemia present in infants.

SYMPTOMS

 Lethargy

 Fatigue

Incessant crying due to orotic acid crystals in ureter produces colicky pain

Growth retardation

SIGNS

Tachycardia and faint murmur due to hyperdynamic circulation in anemia.

LABORATORY INVESTIGATION:

Urine analysis show orotic acid crystals.

Peripheral blood smear show hypochromic megaloblastic anemia and hypersegmented neutrophils.

We can distinguish this increase in orotic acid secondary to OTC deficiency from hereditary orotic aciduria by looking at blood ammonia levels and the BUN (blood urea nitrogen).

HYPERAMMONAEMIA is present in OTC deficiency.

TREATMENT

Administration of uridine, which is converted to UMP, will bypass the metabolic block and provide the body with a source of pyrimidine. Uridine triacetate is a drug approved by FDA to be used in the treatment of hereditary orotic aciduria.

Have a great day.

-Upasana Y. :)

Mechanistic insights regarding Lesch-Nyhan syndrome

Hello friends! Let's refresh our biochemistry knowledge today.

Lesch-Nyhan syndrome is characterized by choreoathetosis, dystonia, hyperuricemia, gout, self mutilatory behavior especially self-biting of fingers, and intellectual disability due to HGPRTase mutations.

So how do HGPRTase mutations actually cause dystonia and other extrapyramidal signs and symptoms?

1.)  For the synthesis of dopamine tetrahydrobiopterin as a cofactor for tyrosine hydroxylase is required.
Tetrahydrobiopterin itself is derived by a series of reactions in which GTP cyclohydrolase is a rate-limiting enzyme.
Now HGPRTase deficiency causes depletion of GTP thereby ultimately depleting tetrahydrobiopterin.

In fact, GTP cyclohydrolase mutations are known to cause dopa-responsive dystonia and phenotype similar to Lesch-Nyhan syndrome.

2.)  Secondly, dopamine receptors are linked to G-protein coupled receptors which alternate between GTP-GDP bound states, yet another link between GTP depletion and perturbation of dopamine signaling.

3.) Adenosine deficiency due to the reduction in salvage may adversely affect the role of adenosine as a neuroprotective agent.

Lastly, in Lesch Nyhan syndrome no characteristic imaging abnormalities are seen but reduced dendritic arborizations in the caudate nucleus, putamen, and nucleus accumbens are thought to underlie clinical manifestations.

So to summarise, Lesch Nyhan syndrome can be considered as one of the basal ganglia disorders with Wilson's disease and Huntington's disease being the other notable ones.

Have a great day!

-Kirtan Patolia

Cyanide poisoning

Cyanide is a mitochondrial toxin that causes death within minutes to hours of exposure.

PATHOPHYSIOLOGY:

1)Cyanide avidly binds to the ferric ion (Fe3+) of complex IV thus inhibiting the Electron transport chain.

2)The cell must then switch to anaerobic metabolism of glucose to generate ATP.Anaerobic metabolism leads to the formation of lactic acid and the development of metabolic acidosis.

TREATMENT:

1)Sodium nitrite and Amyl nitrite induce formation of methemoglobin. Cyanide has high affinity to metHb. This provides an attractive alternative binding site for cyanide which makes the ETC free.

2)Sodium thiosulfate can be given which converts cyanomethemoglobin to thiocyanate and metHb. Thiocyanate is then renally excreted and metHb can be converted back to normal Hb by using methylene blue.

3) Hydroxocobalamin, a precursor of vitamin B12, avidly binds to intracellular cyanide (with greater affinity than cytochrome oxidase) forming cyanocobalamin. This molecule is stable and readily excreted in the urine.

-Srikar Sama

Early morning workout and weight loss.

To reduce weight, early morning exercise is recommended but question is why?
Let's get back to basics before answering this question.

Body has three sources of blood glucose to maintain level uniformly.
1) Food.
2) Liver Glycogen.
3) ‎Gluconeogenesis.

Now, Liver Glycogen can provide energy for around 12-18 hours. Gluconeogenesis uses lots of energy to maintain blood glucose level. Between dinner and breakfast we have gap of around 12 hours. This mean before taking breakfast  liver glycogen stock is null! And body is using now gluconeogenesis to maintain blood glucose level and as you know it's going to take hell lots of ATPs to maintain it. Also, exercise uses lots of energy. Hence both in turn helps in reducing body weight.

What is wrong with evening workout?

Suppose a person has taken lunch around 2 pm and he's working out around 5-6 pm. Which stores will be used by body to maintain glucose level - food obviously! Hardly any Liver glycogen is used up. Also extra food will be stored.

That's all!

-Demotional bloke

Obesity in Prader-Willi syndrome and WAGR syndrome

The delicate balance between food consumption and energy expenditure involves the modulation of orexigenic and anorexigenic signals at the hypothalamus.

OREXIGENIC PATHWAY- It involves peripheral mediators like ghrelin and neuropeptide-Y. 

They act on NPY-AgRP(neuropeptide-Y and agouti-related peptide) neurons which subsequently mediates orexigenic signals via second-order neurons that release peptides like orexin at the hypothalamus.

ANOREXIGENIC PATHWAY- It involves peripheral mediators like leptin, amylin, and PYY(Peptide YY).

They act on POMC/CART(Pro-opio melanocortin/Cocaine and amphetamine-regulated transcript) neurons.

These neurons release an alpha-melanocyte-stimulating hormone which in turn stimulates second-order neurons that release TRH, CRH and hence mediate catabolism.

They also simultaneously inhibit the anabolic pathway.

Now back to the pathogenesis of obesity in these syndromes.

In Prader-Willi syndrome levels of PYY are low due to loss of imprinted genes on chromosome 15q11-q13.

This results in reduced catabolism and enhanced uninhibited anabolism.

It is not uncommon for such patients to have BMI above 40.

In WAGR syndrome there is haploinsufficiency of BDNF(Brain-derived neurotrophic factor).

Alpha melanocyte-stimulating hormone in the catabolic pathway acts through melanocortin receptors(MC4R) on second-order neurons.

Downstream signaling pathways of MC4R involve BDNF hence explaining obesity in these patients.

In fact, efforts are already underway to reduce PPY levels and modulate BDNF to control obesity in these disorders.

Kirtan Patolia

Talazoparib: Zenith of novelty

Recently, talazoparib was approved by FDA for BRCA mutated breast cancer. Several other drugs related to it such as niraparib, olaparib are already approved for ovarian and breast cancer.

So how they work:

In eukaryotic cells, there is highly intricated network of sensors, transducers and mediators for DNA damage recognition and subsequent successful repair.

One of the such molecule is PARP (polyADP ribose polymerase) which serves to identify single strand breaks (SSBs) and seal them.

If PARP is inhibited (say, by talazoparib) then SSBs would progress to double strand breaks (DSBs). DSBs can also be effectively repaired by BRCA 1 and BRCA 2 complex by homologous recombination method.

However, in cancer cells with mutated BRCA, DSBs would not be repaired, ultimately causing apoptosis via molecules such as PUMA (p53 upregulated modulator of apoptosis), NOXA and p21.

Furthermore, talazoparib is known to induce formation of cytotoxic PARP-DNA complex, further contributing to it's mechanism.

That is definitely zenith of novel mechanism.

Transcription : A mnemonic to remember the RNA Polymerases

Here's a short mnemonic post for you!

Transcription is the process by which the DNA is converted into an RNA transcript ( Literally - the DNA is transcribed or written out as an RNA sequence).

The key enzyme needed for this process is RNA Polymerase.

In Eukaryotes , there are 3 different RNA Polymerases subtypes depending on which RNA they help code for. 

We know that Ribo Nucleic Acids or RNA can be mRNA - Messenger RNA , tRNA or Transfer RNA , rRNA - Ribsomal RNA or one of the small nuclear RNAs - micro RNA - miRNA / siRNA.

Here's a mnemonic to memorize which RNA Polymerase codes for which of these -

Mnemonic - R MIS T5 (Read as R Mistify)

RNA Polymerase I = rRNA
RNA Polymerase II = mRNA, miRNAs , siRNAs
RNA Polymerase III = tRNA , 5S rRNA

This form of RNA specificity is not found on the Prokaryotes - and they have just one RNA Polymerase that bears it all , for all types of RNA !

This has been a quick summary of transcription and a helpful mnemonic for you!

Hope was helpful.
Stay awesome !
Happy Studying!

~ A.P.Burkholderia

Features of DNA replication: Semiconservative replication

Hello everyone!

Here is a feature of DNA replication that we don't think much about - the semiconservative replication!

Features of DNA replication: Unidirectionality and bidirectionality

Hello everyone!

DNA replication can be unidirectional or bidirectional, depending upon whether the replication from the point of origin proceeds only in one direction or proceeds in both the directions.

Pyruvate Carboxylase Vs Pyruvate Dehydrogenase (a mnemonic)

Biochemistry has a lot of enzymes and equations which may make it hard to memorize!
Mnemonics come in handy and make our lives easier :D

I used to mix the function of these two enzymes: PC (Pyruvate Carboxylase) and PD ( Pyruvate Dehydrogenase)
so let’s first write the “simplified equations" with their main outcomes then talk about the mnemonic:

Pyruvate ---Pyruvate Carboxylase → OXloacetate

Pyruvate --Pyruvate Dehydrogenase→ Acetyl-CoA

A good way to remember that PC gives Oxaloacetate is just saying: PC and Xbox ( 2 platforms used for gaming) with the X in Xbox referring to the X in oXaloacetate.

To remember that PD gives Acetyl-CoA, put in mind that we become DEHYRATED in HOT weather so we use AIR CONDITIONERS  (ACs).
Dehydrogenase in Pyruvate dehydrogenase will remind you of dehydration and the need of ACs, consider AC the acronym of Acetyl-CoA ;)

A friend drew this to help simplifying it:

And that’s it :)

-Murad

Authors diary: Octopus and tyrosinase

Hey everyone!

Here's another way I study - when I am looking up cool things in other creatures, I compare it to the human body. It's fun!

Thiamine and Beri-Beri: A Summary

• Vitamin B1 is Thiamine.

(TCA = TriCarboxylic Acid cycle aka Kreb's cycle ; LDH = Lactate Dehydrogenase ; PDH = Pyruvate Dehydrogenase ; TPP = Thiamine PyroPhosphate)

• Peripheral neuropathy in dry beri-beri is symmetric, sensorimotor, distal > proximal and non-inflammatory demyelinating type.

• Wernicke's syndrome is reversible early while Korsakoff psychosis is reversible in only 20% cases.

• Wernicke-Korsakoff syndrome has typical damage to dorsomedial nucleus of thalamus and mamillary bodies.

• Clinical manifestations of B1 deficiency is worsened by glucose load! As seen in pathophysiology, excess of glucose with relative or absolute deficiency of B1 - as TPP - causes diversion from the preferred PDH pathway (linked to TCA), to the LDH pathway causing life-threatening lactic acidosis. Hence, in a patient with alcohol intoxication/ chronic alcoholism a B1+glucose cocktail is given as they usually are deficient in B1.

Biochemistry pearl: Other co-factors in PDH pathway alongside TPP are Lipoic acid, Coenzyme A, FAD(H) and NAD(H).

DIAGNOSIS:

Clinical diagnosis with confirmatory lab work - that includes:

• Diagnostic - Blood or RBC transketolase activity and increase after intramuscular B1 administration
• Supportive - Blood thiamine, pyruvate and lactate levels

MANAGEMENT:

You give what the patient lacks. An acceptable regimen is:

Injection B1 100 mg intramuscular for 1 week

followed by

Tablet B1 10 mg once-daily per-oral for 1 month.

Let me know if anything needs clarification. Happy studying!

--Ashish Singh.

Metabolism of HDL notes

Hello, 

Here is a short post on the metabolism of HDL.

Transamination

Have you ever wondered about the difference between non-essential and essential amino acids? 

I’m pretty sure you know the difference :))

If non-essential amino acids are not delivered to the body through diet then how are they made in the body? 

Answer is simple it is by the process of transamination

I hope my notes will help you! If you have any doubts, don’t hesitate to comment or send a message on WhatsApp group :)

Heme Synthesis Mnemonic

Hello Everyone!

Lets discuss heme synthesis today.  Here's the Pathway:

That's all,
Thankyou
 -Chai

Tay Sachs Disease

Hello Awesomites!
Here's a Blog on Tay Sachs Disease and some common questions related to it.

Tay-Sachs disease

It is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. Tay–Sachs disease is caused by a genetic mutation in the HEXA genes on chromosome 15. It is inherited from a person's parents in an autosomal recessive manner. The mutation results in problems with an enzyme called beta-hexosamidase A ,located on lysosomes,which results in the build up of the toxin GM2 ganglioside within cells. The most common type, known as infantile Tay–Sachs disease, becomes apparent around three to six months of age with the baby losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move. An eye abnormality called a cherry-red spot, which can be identified with an eye examination, is characteristic of this disorder. Death usually occurs in early childhood. Less commonly the disease may occur in later childhood or adulthood. These forms are generally milder in nature.Diagnosis is by measuring the blood hexosaminidase A level or genetic testing.

Frequently asked questions -

The substance which accumulates in Tay Sach’s disease is Ganglioside.
Deficiency of enzyme Hexosaminidase-A causes Tay Sach’s disease.
Cherry red spot at macula may be seen in Tay Sach’s disease.

That's all!
Thank you.

MD Mobarak Hussain (Maahii)

Tay-Sachs disease notes and mnemonic

Hello!

Tay-Sachs disease is an autosomal recessive, neurodegenerative disease.