Sunday 30 October 2011

Human mitochondria and mtDNA

HUMAN MITOCHONDRIA


Functions of Mitochondria
  1. Mitochondria are the "powerhouses" of the cells as they are the site of Oxidative Phosphorylation (OXPHOS) and ATP production (generation of ATP). 
  2. Mitochondria are required for cell proliferation. Lack of mitochondria leads to no cell proliferation. Cells cannot reproduce without mitochondria.
  3. Mitochondria are responsible for programmed cell death (apoptosis)  - This will be studied in Year 2 Medicine. 
Unwanted Activities of Mitochondria
  1. Mitochondrial activity is also responsible for the (unwanted) generation of reactive oxygen species (ROS) which are implicated in neurogenerative diseases, metabolic diseases and also many types of cancer.
  2. Mitochondria are associated with the development and progression of cancer.
Mitochondrial Nucleic Acids
  1. Mitochondrial nucleic acids resemble bacterial nucleic acids
Mitochondrial DNA (mtDNA)
  1. Mitochondrial DNA (mtDNA) is present in mitochondria
  2. Mitochondrial DNA (mtDNA) is circular
  3. MtDNA is 16,569 basepairs (bp) (or approx. 16,500 nucleotides)
  4. MtDNA is present as multiple copies within an individual cell
  5. MtDNA encodes 13 essential polypeptides which are part of the OXPHOS complexes, as well as 22 tRNAs and 2 rRNAs
  6. MtDNA has information to code for the synthesis of 2 ribosomal RNAs (rRNAs), 22 tRNAs and 13 proteins, all of which are components of the electron transport chain (ETC)
  7. Most mitochondrial proteins are encoded by nuclear DNA (nDNA) and are synthesized in the cytoplasm
Dichotomy of Mitochondrial Metabolism
  1. Some mitochondrial protein synthesis is under the control of mitochondrial DNA (mtDNA)
  2. Important proteins of the outer membrane of the mitochondria  are synthesized under the influence of nuclear DNA (nDNA)

External Links
  1. Wikipedia. Mitochondria
  2. Wikipedia. Cambridge Reference Sequence
  3. Nature 290, 457 - 465 (09 April 1981); doi:10.1038/290457a0. Sequence and organization of the human mitochondrial genome
Textbook

Textbook of Biochemistry (For Medical Students), Third Edition, 2004, p416.

Tuesday 25 October 2011

Muscular activity: Energy requirement and Cori cycle



Muscular activity requires energy, which is provided by the breakdown of glycogen in the skeletal muscles. The breakdown of glycogen, a process known as glycogenolysis, releases glucose in the form of glucose-6-phosphate (G-6-P). G-6-P is readily fed into glycolysis, a process that provides ATP to the muscle cells as an energy source. During muscular activity, the store of ATP needs to be constantly replenished. When the supply of oxygen is sufficient, this energy comes from feeding pyruvate, one product of glycolysis, into the Krebs cycle.

When oxygen supply is insufficient, typically during intense muscular activity, energy must be released through anaerobic respiration. Anaerobic respiration converts pyruvate to lactate by lactate dehydrogenase. Most important, fermentation regenerates NAD+, maintaining the NAD+ concentration so that additional glycolysis reactions can occur. The fermentation step oxidizes the NADH produced by glycolysis back to NAD+, transferring two electrons from NADH to reduce pyruvate into lactate. Refer to the main articles on glycolysis and fermentation for the details

Instead of accumulating inside the muscle cells, lactate produced by anaerobic fermentation is taken up by the liver. This initiates the other half of the Cori cycle. In the liver, gluconeogenesis occurs. From an intuitive perspective, gluconeogenesis reverses both glycolysis and fermentation by converting lactate first into pyruvate, and finally back to glucose. The glucose is then supplied to the muscles through the bloodstream; it is ready to be fed into further glycolysis reactions. If muscle activity has stopped, the glucose is used to replenish the supplies of glycogen through glycogenesis.

Anaerobic metabolism: Cori cycle


After completion of this learning unit, you should be able to answer the following questions.

What is the Cori cycle?
When does it work?
What does it do?
Why is it important?


The Cori cycle (also known as Lactic acid cycle), named after its discoverers, Carl Cori and Gerty Cori, refers to the metabolic pathway in which lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is converted back to lactate.

The Cori cycle invloves the utilization of lactate, produced by glycolysis in non-hepatic tissues, (such as muscle and erythrocytes) as a carbon source for hepatic gluconeogenesis. In this way the liver can convert the anaerobic byproduct of glycolysis (lactate), back into more glucose for reuse by non-hepatic tissues. Note that the gluconeogenic leg of the cycle (on its own) is a net consumer of energy, costing the body 4 moles of ATP more than are produced during glycolysis. Therefore, the cycle cannot be sustained indefinitely.

Under anaerobic conditions, glucose is metabolized through glycolysis which converts it to two molecules of pyruvate. Only one oxidation step has been performed when glyceraldehyde 3-phospate is oxidized to 1,3-bisphosphoglycerate. To regenerate NAD+ so glycolysis can continue, pyruvate is reduced to lactate, catalyzed by lactate dehydrogenae.   These reactions take place in the cytoplasm of cells actively engaged in anaerobic oxidation of glucose (in yeast; in muscle cells during sprint).   Note that the enzyme is named for the reverse reaction, the oxidation of lactate by NAD+.

The cycle's importance is based on the prevention of lactic acidosis in the muscle under anaerobic conditions. However, normally before this happens the lactic acid is moved out of the muscles and into the liver. The cycle is also important in producing ATP, an energy source, during muscle activity. The Cori cycle functions more efficiently when muscle activity has ceased. This allows the oxygen debt to be repaid such that the Krebs cycle and electron transport chain can produce energy at peak efficiency.



Pathways of Metabolism

 Metabolism

   Carbohydrate Metabolism

   Energy Metabolism

     00190  Oxidative phosphorylation
     00910  Nitrogen metabolism
     00920  Sulfur metabolism

   Lipid Metabolism

   Nucleotide Metabolism (nucleic acids - DNA, RNA)

   Amino Acid Metabolism

   Metabolism of Other Amino Acids

   Glycan Biosynthesis and Metabolism (Master of Medicine - Chemical Pathology)

   Metabolism of Cofactors and Vitamins

   Metabolism of Terpenoids and Polyketides (not covered in Year 1 Biochemistry)

   Biosynthesis of Other Secondary Metabolites

   Xenobiotics Biodegradation and Metabolism (covered by Pharmacology)

   Overview


Genetic Information Processing (Genetics Block)

 Environmental Information Processing

 Cellular Processes (covered by Chemical Pathology, Physiology and Pathology)

 Organismal Systems

 Human Diseases (Introductory in Year 1)

 Drug Development (not taught in undergraduate medicine)

Source: Kegg Brite pathway maps

Electron Transport Chain (ETC) - Protein components; oxidative phosphorylation; reactions; inhibitors

Electron Transport Chain (ETC) 

Electron Transport Chain - components

Synonym: Electron Transport System (ETS)

ATP and Oxidative Phosphorylation

Oxidative Reactions: Dehydrogenases and Oxidases

Inhibitors of Oxidative Phosphorylation

Several chemicals can block electron transfer in ETS, or transfer of electrons to oxygen. All are strong poisons. Examples are:
  1.         Carbon monoxide (CO) -- combines directly with terminal cytochrome oxidase, blocks oxygen attachment.
  2.         Cyanide (CN-) and Azide (N3-) bind to cytochrome iron atoms, prevent electron transfer.
  3.         Antimycin A (an antibiotic) inhibits electron transfer between cyt b and c. 

Animations and videos

http://tube.medchrome.com/2012/04/electron-transport-chain-and-oxidative.html

https://www.youtube.com/watch?v=Fcu_8URp4Ac

SGD: Energy Metabolism in Muscle - sources of energy for muscle contraction

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SGD
1. List the sources of energy that can be used for muscle contraction. Explain briefly how energy is derived from these energy sources.

SGD: Energy Metabolism in Muscle - plasma lactate rises after exercise

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SGD
2. Explain why plasma lactate level increases after prolonged and severe muscular exercise.

SGD: Energy Metabolim in Muscle - Beta-oxidation of palmitic acid (C16)

Musculoskeletal Block, MD Phase I 2011/2012Prepared by Dr Aini Suzana Adenan
17 October 2011

SGD
3. What is the net number of ATP produced in beta-oxidation of palmitic acid (C16)? Show the calculation.

SGD: Energy Metabolism in Muscle - TCA cycle amphibolic pathway

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SGD
4. Give the reasons for calling the TCA cycle as an amphibolic pathway. Name the various substances produced from the following TCA cycle intermediates:


a. Succinyl CoA --> Heme


b. Citrate --> Fatty acids


c. alpha-Ketoglutarate --> Glutamate


d. Oxaloacetate --> Glucose


e. Oxaloacetate --> Aspartate

SGD: Energy Metabolism in Muscle - TCA cycle is aerobic pathway

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SGD
5. Give reasons why TCA cycle is an aerobic pathway even though oxygen is not involved directly in its reactions.

SGD: Energy Metabolism in Muscle - Chemiosmotic theory, oxidative phosphorylation, ATP generation

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SGD
6. Explain the chemiosmotic theory of oxidative phosphorylation in the generation of ATP.

SGD: Enery Metabolism in Muscle - Inhibitors and mutations of ETC proteins

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SGD
7. Inhibitors of the electron transport chain proteins and mutations in the mitochondrial and nuclear DNA that encodes them can cause reduced activity of the electron transport chain. Explain why impairment of the electron transport chain can cause lactic acidosis.

Aerobic & Anaerobic Pathways in Muscles

Musculoskeletal Block, MD Phase I 2011/2012

SLU: Energy Metabolism in Muscle - Aerobic and anaerobic pathways

Prepared by Dr Aini Suzana Adenan
17 October 2011


1. Name the aerobic and anaerobic pathways involved in the production of energy in the muscle cells.

Aerobic:


Anaerobic:

ATP Production in Muscle

Musculoskeletal Block, MD Phase I 2011/2012

SLU: Energy Metabolism in Muscle - ATP production

Prepared by Dr Aini Suzana Adenan
17 October 2011


2. How many ATPs are produced in the catabolism of:

a. glucose to pyruvate?

b. glucose to carbon dioxide and water (complete oxidation) in liver and muscle?

c. glucose to lactate?

SLU: Energy Metabolism in Muscle - Beta-oxidation

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SLU
3. Name the products of one cycle of beta-oxidation.

SLU: Energy Metabolism in Muscle - TCA cycle and NADH, FADH2

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SLU
4. Where do the TCA cycle reactions occur and how many energy-producing substances are formed?

SLU: Energy Metabolism in Muscle - Oxidation of NADH and FADH2

Musculoskeletal Block, MD Phase I 2011/2012
Prepared by Dr Aini Suzana Adenan
17 October 2011

SLU
5. How many ATP molecules are produced in the oxidation of NADH and FADH2 through the electron transport chain (ETC)?

Inhibitors & Uncouplers of ETC

Musculoskeletal Block, MD Phase I 2011/2012

SLU: Energy Metabolism in Muscle - Inhibitors and Uncouplers of ETC

Prepared by Dr Aini Suzana Adenan
17 October 2011


6. Which of the following is an inhibitor or uncoupler of the electron transport chain (ETC)? Explain their mechanism of action.

a. Cyanide (CN-)

b. Carbon monoxide (CO)

c. 2.4-Dinitrophenol (2,4-DNP)

d. Gramicidin

Medical Biochemistry

The Medical Biochemistry Page is here: http://themedicalbiochemistrypage.org/home.html

Traditional & Herbal Medicine

This video covers some medicinal herbs - peria katak, belimbing tanah, sambung nyawa, hempedu bumi, kemuning Cina (periwinkle), etc. The traditional practitioners (& artist) are interviewed. There are 2 success stories - jus peria katak for gastritis; air rebusan pokok belimbing tanah for hypertension. The massage technique looks good - also works for stroke.

Pusat Rawatan Islam Al-Hidayah

Dear students,

I did not have time to teach you in detail on the topic of Islamic Medicine - Quranic Medicine & Prophetic Medicine. I'm still searching. There are websites that touch on these topics.

Here is information on Quranic Medicine.
http://www.alhidayah-medic.com/prosedur-rawatan/Page-4-1.html

If you visit the page, you will see many conditions listed. There are basically 6 categories of conditions that they treat: pediatric, terminal, fertility, mental/psychological disturbances, addiction, and medical problems.

Pediatric cases include:
Down Syndrome, nephrotic syndrome, cerebral palsy, hydrocephalus, hyperactive, and late brain development.

Terminal conditions include:
Cancers, systemic Lupus erythematosus (SLE), AIDS and HIV.

Fertility problems include:
Fibroid, ovarian cyst, endometriosis, and low sperm count.

Mental/Psychological conditions include:
Conditons resulting from sihir jin, syaitan and iblis, saka, santau, rasuk, susuk, and depression.

Addiction cases include:
Drug addiction, gambling, and alcoholism.

Other cases include:
Diabetes, hypertension, heart problems, gallstones, renal/kidney problems, epilepsy, rheumatism, hepatitis and neurological problems.

My comments:

DIABETES is kencing manis. There is presently no 100% cure known for diabetes nor can the condition be reversed 100% nor does it go away for good. But the condition can be controlled in many ways, for which patients perceived themselves as "cured" or even "cured for good". Death from diabetes is inevitable in the long run but patients die from complications of diabetes, not diabetes itself (i.e., not diabetes per se). Control measures include dietary restrictions, especially carbohydrate intake - there is a need to reduce the amount of rice taken - major source of carbohydrate in our Malaysian diet. The type of rice used and the way the rice is cooked also matter. The usual rice that we take (beras Siam #1 or any of the Malaysian rice variety) is rich in carbohydrate. The rice can be cooked in the usual manner but half way through cooking, the rice water needs to be drained (discarded) and fresh boiled water can be added. The rice is left to cook. This will remove starch from the rice and give a bland taste to the rice (nasi rasa payau). When cooked in this way, the patient can still consume the rice and body weight is easier to control. Another way is to switch to Beras Basmati (or beras wangi). This is an Indian rice variety and is grown in India where the soil is rich in calcium. The rice contains little starch. The patient can eat this rice but because this calcium-rich rice is tasteless, patients tend to eat very little rice. This rice has a plus point - it takes away hunger, i.e., patients only need to eat a little Basmati rice and this will make them feel full for a long time, so patients tend to lose weight rather than gain weight. The Indians eat this rice and can work all day long without additional food between meals.

HYPERTENSION needs proper attention. We eat rice with other accompanying dishes (lauk). Rice is unsalted but the accompanying dishes are what give us a lot of problems. We don't seem to be able to control our salt intake. Salt is usually added to our dishes during cooking, so we have to get the cooks/chefs to control how much salt they add to our food while cooking. But because a lot of the food we eat today are buffet style, they need to last longer than normal, for extended eating times. As such cooks/chefs add more salt to food than necessary so food last longer especially for buffets. There are too other appetizers and condiments are which are salty - ikan bilis, ikan masin, sambal belacan, etc. There are also salted eggs and salted vegetables. It will be better to control intake of these foods in order to avoid hypertension or to help control hypertension. The other source of hypertension is STRESS - exam stress (for students), love stress (for couples), work stress (for working adults), old-age stress (for elderly) and other stress of various sorts.

HEART problems can be an underlying disease and undetectable for a long time (chronic process). When it does show clinical symptoms (what the doctors can detect and therefore investigate), it is too late and often it is irreversible. Surgery is the next best alternative. So prevention is better than cure. Prevention covers 3 aspects - food, exercise and attitude (mood). Good healthy clean nutritious food is best. Constant exercise or movements are good for the muscles and bones. Having a positive attitude and being happy is the best cure for all human problems relating to the heart. Of course a dead heart (a deceased person) can't wake up! The opposite of being happy is being depressed. So try to adjust life to be more on the happy side and enjoy life, but within limits (not beyond limits). You can jump or bounce high, but you still need to keep your feet on the ground. Life has rules - stick to the rules in life. You break the rules, you suffer the consequences. You have yourself to blame for whatever goes wrong with your body, including heart problems. So live safely, healthily and be happy - to guard your own heart. Don't create unnecessary heartache and get heart problems. Heart attack (myocardial infarction or MI) can be avoided. Heart problems are created after all.

GALLSTONES are worth studying. Dietary change is a key means to overcoming gallstones. There are now 3 cures known for gallstones:
(i) Surgical removal of the gallbladder (cholescystectomy) - this procedure costs RM3,000.00
(ii) Take olive oil for 3 days until the gallstones dissolve - cheap; olive oil is RM25 per bottle.
(iii) Quranic Medicine - cheap; RM10 per appointment
External link:
http://www.healthline.com/health/gallstones#Overview1

Prof Faridah
25 October 2011
12 October 2014

Thursday 13 October 2011

Pre-SCL Survey

Dear USM students & lecturers,

I'm helping Prof Abdul Karim with his survey. Be a sport and take his survey if you are a USM student or lecturer. Do it before the deadline, 30 October 2011. Please tell your friends.

TQ

Prof Faridah
--
 The following are his 2 e-mails re the survey. Please take the survey if you are a USM student/lecturer.
--
First e-mail:

Kepada semua penulis modul yang dihormati,

Nak minta tolong sikit. I would be grateful if you could spare some of your precious time to do the above survey. Data from this survey will help the university to formulate strategic transformation plan for P&P. Please also request you students (by announcing it in the lecture or blast the email to students' mailing list) to do the survey. I'm trying my best to reach maximum number of respondents (lecturers & students) via various channels.

Many thanks for your help!

Karim
--
Second e-mail

Dear all,

Thousand apologies...lupa nak bagi link. Here's the announcement for the survey and the link:

USM sedang dalam usaha untuk mentransformasikan kaedah Pengajaran dan Pembelajaran (P&P) selaras dengan plan transformasi APEX dan dasar P&P yang telah ditetapkan oleh Kementerian Pengajian Tinggi. Untuk itu, J/K Senat Khas Pelan Transformasi P&P USM yang dipengerusikan oleh Profesor Abd Karim Alias memerlukan data tentang kaedah P&P yang sedang dipraktikkan oleh pensyarah. Kerjasama pensyarah dan pelajar adalah amat diharapkan untuk melengkapkan soal selidik yang terdapat di pautan berikut sebelum 30 Oktober 2011:

Untuk pensyarah:
http://www.surveygizmo.com/s3/622345/Questionnaire-for-lecturers

Untuk pelajar:
http://www.surveygizmo.com/s3/
622343/Questionnaire-for-students

Mohon kerjasama semua pensyarah untuk menghebahkan survey ini kepada semua pelajar dalam kuliah masing-masing. Link kepada survey ini juga boleh dicapai apabila pensyarah atau pelajar login ke dalam e-learning portal USM bagi kursus masing-masing.

Respon kepada soal selidik ini amat berguna dan penting bagi memberi panduan kepada jawatankuasa merangka suatu pelan transformasi yang mantap dan berkesan.

Sekian, terima kasih.

Karim
------------------------------
Professor Abd Karim Alias
Food Technology Division
School of Industrial Technology
Universiti Sains Malaysia
11800 Penang
Malaysia

Personal website: http://www.indtech.usm.my/karim/AKA/Home.html
Visit my blog: http://onestoplearning.blogspot.com/

Tel: 6046532221
Fax: 6046573678
HP: 019-4408242
------------------------------------------------


Saturday 8 October 2011

TNC HEA&A - Prof Ahmad Shukri Mustapa Kamal

Bengkel Penulisan Modul Pengajaran & Pembelajaran USM
7-9 Oktober 2011
Park Royal Penang Resort, Batu Ferringhi
Pulau Pinang


TNC HEA&A's Speech

Majlis Perasmian oleh YBhg Prof Ahmad Shukri Mustapa Kamal

What transpired ...

Every teacher teaches differently. Some lecturers come to class and write continuously on the transparency (rolled type) and talk/explains without looking at the students. Some come to class and sit on the front desk and start talking, telling stories and asking questions; there are no notes, slides, etc. Some come to class and immediately write questions on the blackboard and the students must work on the problems he wrote on the board.

No senior lecturer will strictly follow a "How to Teach Guide", including Student-Centred Learning (SCL).

Whatever students complain against lecturers to the Dean, the Dean can take action and talk to the lecturers concerned. There will always be a small number of lecturers who are strict and students fail their class, every year.

Lecturers do expect students to be able to do their own reading and be prepared for class but do students know this?

Vietnamese are noted for their mathematical skills. Malaysians can learn from their Vietnamese counterparts.

Just to add my notes: 

French make good mathematicians. The French language is fast, simple with short syllables and makes thinking and speaking fast. Thus French and French speakers tend to be good mathematicians. Vietnamese are French-speaking people. So like their conquerors, they make good mathematicians. However, French aerospace engineering has suffered a lot despite French being good mathematicians. Remember the last of the Concords? Is any flying around today? Concord is French? What happened to Concord? Its pointed nose fell off at take off?

Anyway, respect is still due to all lecturers/professors regardless of their teaching styles. No one particular style will fit everyone.

Do not blame yourself for poor learning. It is just that you did not make full use of your time, effort and capabilities while still within the university system. You still have time to learn. Learning is lifelong.

Technology evolves and so do teaching and learning styles. Nothing remains the same. Some do eventually become obsolete.

Not being techno-savvy should not mean lecturers/professors from the older generation are no good or useless. Quite the contrary occurs in the real world. Lecturer/professors from the older generation have the resources and means (i.e., $) for purchasing technological products/gadgets. So they will tend to be techno-savvy than the younger generation. Of course the younger generation like and want some technological gadgets and they go all out to purchase their dream machines. However, the younger generation have a limited cash supply or reserve and can sometimes only make one such purchase. So in the long run, the younger generation often jump in to purchase what they perceive as a necessary gadget and purchase it right away - it will be their first and also last purchase as they do not have a large cash reserve to make another purchase anymore.

Do not be deceived by young people showing off their new techno gadgets - that's all they have anyway. Instead, go to the older generation who more often than not, have more cash reserve than they will ever need for their remaining life on earth and can afford to waste $ on techno gadgets that they actually do not need. Tell me, which scraggly old man needs a brightly coloured smartphone that says repeatedly, "It's me honey!" and flashes an image of his fatally beautiful dream woman every time a call comes in and the phone rings? Old as he may be, he is in twilight zone with his right foot in the dark zone - i.e., at the end of his phase in life on earth. What is there to look forward to when one is at the brim of death? Don't tell me that smartphones get buried with their owners?! The world must crazy if that holds true!

Prof Faridah

Wednesday 5 October 2011

Anion Gap

Introduction

The anion gap is the difference in the measured cations and the measured anions in serum, plasma, or urine. The magnitude of this difference (i.e. "gap") in the serum is often calculated in medicine when attempting to identify the cause of metabolic acidosis. If the gap is greater than normal, then high anion gap metabolic acidosis is diagnosed.

The term "anion gap" usually implies "serum anion gap", but the urine anion gap is also a clinically useful measure.

Calculations

Determination of serum cations include Sodium (Na+) and Potassium (K+).  Calcium (Ca2+) and Magnesium (Mg2+) values are rarely used (as these are doubly-charged ions).

Determination of serum anions include Chloride (Cl) and Bicarbonate (HCO3). Phosphates and sulphates are not determined.


The old concentrations were expressed in units of milliequivalents/liter (mEq/L). The more recent and preferred way is to express all components in millimoles/litre (mmol/L).

There is a simple formula for calculating anion gap, that uses a potassium term or the potassium term can be omitted altogether.

 

With potassium included in the calculation

It is calculated by subtracting the serum concentrations of negatively-charged ions chloride and bicarbonate (anions) from the concentrations of positively-charged ions sodium and potassium (cations):
Anion Gap = [Na+] + [K+] − [Cl] − [HCO3]

Without potassium included in the calculation (Daily practice)

However, the potassium is frequently ignored because potassium concentrations, being very low, usually have little effect on the calculated anion gap. This leaves the following equation:
Anion Gap = [Na+] − [Cl] − [HCO3]
Uses

Anion gap is an 'artificial' and calculated measure that is representative of the unmeasured ions in plasma or serum (serum levels are used more often in clinical practice).

Commonly measured cations include Sodium (Na+), Potassium (K+), Calcium (Ca2+) and Magnesium (Mg2+).

Cations that are generally considered 'unmeasured' include a few normally occurring serum proteins, and some pathological proteins (e.g., paraproteins found in multiple myeloma).

Likewise, commonly 'measured' anions include chloride (Cl), bicarbonate (HCO3) and phosphate (H2PO4), while commonly 'unmeasured' anions include sulphates and a number of serum proteins.

By definition, only Na+, Cl and HCO3 (+/- K) are used when calculating the anion gap.

In normal health there are more measurable cations compared to measurable anions in the serum; therefore, the anion gap is usually positive. Because we know that plasma is electro-neutral we can conclude that the anion gap calculation represents the concentration of unmeasured anions.

The anion gap varies in response to changes in the concentrations of the above-mentioned serum components that contribute to the acid-base balance.

Calculating the anion gap is clinically useful, as it helps in the differential diagnosis of a number of disease states.

Reference values (Reference range; Normal values; Normal value ranges)

Modern analyzers make use of ion-selective electrodes (ISE) which give a normal anion gap as <11 mmol/L. Therefore according to the new classification system a high anion gap is anything above 11 mmol/L and a normal anion gap is often defined as being within the prediction interval of 3–11 mmol/L, with an average estimated at 6 mmol/L.

In the past, methods for the measurement of the anion gap consisted of colorimetry for [HCO3] and [Cl] as well as flame photometry for [Na+] and [K+]. Thus normal reference values ranged from 8 to 16 mmol/L plasma when not including [K+] and from 10 to 20 mmol/L plasma when including [K+]. Some specific sources use 15 and 8–16 mmol/L.

A reference range provided by the particular lab that performs the testing should be used to determine if the anion gap is outside of the normal range. A certain proportion of normal individuals may have values outside of the 'normal' range provided by any lab.

Interpretation

Anion gap can be classified as either high, normal or, in rare cases, low. Laboratory errors need to be ruled out whenever anion gap calculations lead to results that do not fit the clinical picture.

Methods used to determine the concentrations of some of the ions used to calculate the anion gap may be susceptible to very specific errors. For example, if the blood sample is not processed immediately after it is collected, continued leukocyte cellular metabolism may result in an increase in the HCO3 concentration, and result in a corresponding mild reduction in the anion gap.

In many situations, alterations in renal function (even if mild, e.g., as that caused by dehydration in a patient with diarrhoea) may modify the anion gap that may be expected to arise in a particular pathological condition.

A high anion gap indicates that there is loss of HCO3 without a concurrent increase in Cl. Electroneutrality is maintained by the elevated levels of anions like lactate, beta-hydroxybutyrate and acetoacetate, PO4, and SO4. These anions are not part of the anion-gap calculation and therefore a high anion gap results. Thus, the presence of a high anion gap should result in a search for conditions that lead to an excess of these substances.

HIGH ANION GAP

The anion gap is affected by changes in unmeasured ions. A high anion gap indicates acidosis. e.g. In uncontrolled diabetes, there is an increase in ketoacids (i.e. an increase in unmeasured anions) and a resulting increase in the anion gap. In these conditions, bicarbonate concentrations decrease, in response to the need to buffer the increased presence of acids (as a result of the underlying condition). The bicarbonate is consumed by the unmeasured anion (via its action as a buffer) resulting in a high anion gap.
  • Lactic acidosis
  • Ketoacidosis
    • Diabetic ketoacidosis
    • Alcohol abuse
  • Toxins:
    • Ethylene glycol
    • Lactic acid
    • Uremia
    • Methanol
    • Propylene glycol
    • Phenformin
    • Aspirin
    • Cyanide, coupled with elevated venous oxygenation
    • Iron
    • Isoniazid
  • Renal failure, causes high anion gap acidosis by decreased acid excretion and decreased HCO3 reabsorption. Accumulation of sulfates, phosphates, urate, and hippurate accounts for the high anion gap.
Note: a useful mnemonic to remember this is MUDPILES (methanol, uremia, diabetic ketoacidosis, propylene glycol, isoniazid, lactic acidosis, ethylene glycol, salicylates). A newer mnemonic CUTE DIMPLES includes C for Cyanide and T for Toluene. Historically, the "P" in MUDPILES was for paraldehyde. As paraldehyde is no longer used medically, the "P" in the MUDPILES mnemonic currently refers to propylene glycol, a substance common in pharmaceutical injections such as diazepam or lorazepam. Accumulation of propylene glycol is converted into lactate and pyruvate, which causes lactic acidosis. GOLDMARK standing for glycols, oxoproline, L-lactic acidosis, D-lactic acidosis, methanol, aspirin, renal failure, and ketoacidosis is also used as a mnemonic for the causes of high anion gap in metabolic acidosis.

NORMAL ANION GAP

In patients with a normal anion gap the drop in HCO3 is compensated for almost completely by an increase in Cl and hence is also known as hyperchloremic acidosis. The HCO3 lost is replaced by a chloride anion, and thus there is a normal anion gap.
  • Gastrointestinal loss of HCO3 (i.e., diarrhoea) (note: vomiting causes hypochloraemic alkalosis)
  • Renal loss of HCO3 (i.e. proximal renal tubular acidosis (RTA) also known as type 2 RTA)
  • Renal dysfunction (i.e. distal renal tubular acidosis also known as type 1 RTA)
  • Ingestions
    • Ammonium chloride and Acetazolamide, ifosfamide.
    • Hyperalimentation fluids (i.e. total parenteral nutrition, TPN)
  • Some cases of ketoacidosis, particularly during rehydration with Na+ containing IV solutions.
  • Alcohol (such as ethanol) can cause a high anion gap acidosis in some patients, but a mixed picture in others due to concurrent metabolic alkalosis.
  • Mineralocorticoid deficiency (Addison's disease)
Note: a useful mnemonic to remember this is FUSEDCARS (fistula (pancreatic), uretogastric conduits, saline administration, endocrine (hyperparathyroidism), diarrhea, carbonic anhydrase inhibitors (acetazolamide), ammonium chloride, renal tubular acidosis, spironolactone)

LOW ANION GAP

A low anion gap is frequently caused by hypoalbuminemia. Albumin is a negatively charged protein and its loss from the serum results in the retention of other negatively charged ions such as chloride and bicarbonate. As bicarbonate and chloride anions are used to calculate the anion gap, there is a subsequent decrease in the gap.

In hypoalbuminaemia the anion gap is reduced from between 2.5 to 3 mmol/L per g/dL decrease in serum albumin. Common conditions that reduce serum albumin in the clinical setting are hemorrhage, nephrotic syndrome, intestinal obstruction and liver cirrhosis.

The anion gap is sometimes reduced in multiple myeloma, where there is an increase in plasma IgG (paraproteinaemia).

Corrections can be made for hypoalbuminemia to give an accurate anion gap.


Source:
Anion Gap in Wikipedia


Hyperchloremic acidosis

Introduction  

Hyperchloremic acidosis is a form of metabolic acidosis associated with a normal anion gap, a decrease in plasma bicarbonate concentration, and in an increase in plasma chloride concentration (see anion gap for a fuller explanation).

Causes
  • Renal tubular acidosis failure of HCO3- resorption (i.e., proximal renal tubular acidosis) or failure of H+ secretion (i.e., in distal renal tubular acidosis)
  • Renal failure
  • Gastrointestinal loss of HCO3- with diarrhoea (vomiting will tend to cause hypochloraemic alkalosis).
  • Ingestions
    • Ammonium chloride, Hydrochloric acid
    • Hyperalimentation fluids (i.e., total parenteral nutrition, TPN)
  • Alcohol (such as ethanol) can affect anion gap by inducing alcohol dehydrogenase enzyme.

Source:
Hyperchloremic acidosis in Wikipedia

Evaluation and Treatment of Classic Hypokalemic Distal Renal Tubular Acidosis

Since normal anion gap hyperchloremic metabolic acidosis is a feature in patients with classic dRTA, diagnosis begins with a history and physical examination (PE) to rule out (TRO) other conditions. The condition of the urine gives a lot of clues to the underlying cause and of RTA.

Lab investigation

STEP 1

The laboratory evaluation should be initiated with the examination of the urine.

If the acidosis is the result of an extrarenal disorder, such as diarrhea, the urine will be rich in ammonium. This can easily be disclosed by measuring the urinary electrolytes. There will be considerably more chloride than sodium (plus potassium), usually more than 50 mmol/L. In other words, the anion gap will be minus 50 or more. The missing cation is ammonium. Patients with dRTA or related syndromes typically have more cation than chloride in the urine when they are acidemic, indicating reduced ammonium excretion and, hence, defective acidification. Once the diagnosis of an RTA syndrome has been made, the urinary anion gap has no further use, since it is abnormal in all RTA syndromes.

STEP 2

The next step is to categorize patients according to serum potassium -- those with a low (or normal) serum potassium and those in whom it is elevated. The first group can be further subdivided into those patients in whom the urine pH can be lowered below 5.5 and those in whom it cannot. When proximal RTA has been excluded by measuring fractional bicarbonate excretion at a serum HCO3 greater than 20 mmol/L, distal RTA can be diagnosed with certainty in those whose urine pH is greater than 5.5 at an acid systemic pH.

STEP 3

Patients in whom urine pH can be lowered below 5.5 and in whom a proximal lesion has been ruled out can then be given sodium bicarbonate intravenously; if the urine PCO 2 fails to rise normally, the diagnosis of rate-dependent dRTA can be made.

Children will need alkali therapy for normal growth.

Maintenance on alkali therapy can be for indefinite period in some cases.

Source: More at WebMD

Renal Tubular Acidosis (RTA)

Introduction

Renal tubular acidosis was first described in 1935 by Lightwood and 1936 by Butler et al. in children. Baines et al. first described it in adults in 1945.

Renal Tubular Acidosis (RTA) is a condition characterized by the inability of the kidneys to secrete hydrogen ions (acid) and therefore, cannot maintain acid-base balance.

Renal tubular acidosis is characterized by a normal anion gap and hyperchloremic metabolic acidosis; plasma potassium may be normal, low, or high, depending on the type of RTA.

Renal tubular acidosis (RTA) syndromes are nonuremic defects of urinary acidification. These syndromes differ from uremic acidosis, which is associated with a high anion gap and with enhanced proton secretion by each remaining nephron

MedIndia. Renal Tubular Acidosis is treated using alkaline agents like sodium bicarbonate and sodium citrate or potassium citrate. In some cases, treating the cause helps the patient recover from RTA. Vitamin D may be needed in some cases. The condition should be diagnosed early and treatment instituted to prevent complications. Regular monitoring is also necessary in these patients.


Types of RTA

There are 4 types of RTA based on their molecular mechanisms responsible for the defect in urinary acidification.
  • Type 1 or Classical Distal RTA
  • Type 2 or Proximal RTA
  • Type 3 is a combination of Types 1 and 2 (Type 3 is rare)
  • Type 4 disease or Hyperkalaemic RTA
Type 3 is rarely discussed. Most comparisons of RTA are limited to a comparison of types 1, 2, and 4.

Type 1 or Classical Distal RTA (dRTA)

Wikipedia. Distal RTA (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the cortical collecting duct (CCD) of the distal nephron. This failure of acid secretion may be due to a number of causes, and it leads to an inability to acidify the urine to a pH of less than 5.3. Because renal excretion is the primary means of eliminating acid from the body, there is consequently a tendency towards acidemia. There is an inability to excrete H+ while K+ cannot be reabsorbed, leading to acidemia (as H+ builds up in the body) and hypokalemia (as K+ cannot be reabsorbed). This leads to the clinical features of dRTA;
  • Normal anion gap metabolic acidosis/acidemia
  • Hypokalemia
  • Urinary stone formation (related to alkaline urine, hypercalciuria, and low urinary citrate).
  • Nephrocalcinosis (deposition of calcium in the substance of the kidney)
  • Bone demineralisation (causing rickets in children and osteomalacia in adults)
WebMD. The distal convoluted tubule and the collecting tubule reclaim about 15% of filtered bicarbonate, lower the urine pH to its final value, and titrate most of the nonbicarbonate urinary buffers. [What are these nonbicarbonate urinary buffers?]

FAR. There are 2 types of collecting tubules, cortical collecting tubule (CCT) and medullary collecting tubule (MCT). Acidification of urine occurs at these 2 locations, CCT and MCT. However, different factors govern these acidifications. CCT acidification (of urine) is governed by aldosterone and linked to sodium transport. Aldosterone increases this transepithelial voltage and hence CCT acidification. [Read on Aldosterone metabolism.] MCT acidification (of urine) is not inflenced by aldosterone or linked to sodium transport.

WebMD. In the cortical collecting tubule (CCT), acidification is indirectly coupled to sodium transport and is influenced by transepithelial voltage. Active sodium reabsorption in this nephron segment generates a negative electrical potential difference, which facilitates the active secretion of protons. [What is meant by active sodium reabsorption?]

Acidification in the medullary collecting tubule (MCT) is not influenced by sodium transport and occurs against an electrical gradient. The potential difference in this nephron segment is lumen-positive, most likely the result of active proton secretion. The absolute magnitude of proton secretion is greater in the MCT than in the CCT.

Hydrogen ion secretion is mediated by two proton pumps located in the intercalated cells, an H+-ATPase and an H+,K+-ATPase.

The H+-ATPase is regulated by aldosterone, while the H+,K+-ATPase responds inversely to the serum potassium level.

In the tubular lumen, the secreted hydrogen ions combine with ammonia and other urinary buffers and are excreted in urine. [Please refer to past year's lecture notes for these reactions.]

FAR. Note that the resultant level of potassium in blood is dependent on the nature and location of the renal tubular defect. In some defects, hypokalemia results; and in other defects, potassium level remains unperturbed, i.e., remains normal.

WebMD. Distal RTA (dRTA) can occur as a result of the following defects:
  • Impaired proton pump function
    • Defective H+,K+-ATPase (classic hypokalemic dRTA) or
    • Defective H+-ATPase (normokalemic dRTA),
  • Decreased potential difference in CCT (or "voltage-dependent" dRTA),
  • Aldosterone deficiency (or resistance),
  • Decreased capacity to maintain steep pH gradients (or "backleak" dRTA),
  • Rate-dependent dRTA, or
  • Abnormal anion exchange.
Classic dRTA is a syndrome of hypokalemia, hyperchloremic metabolic acidosis, inability to lower the urine pH below 5.5, nephrocalcinosis and nephrolithiasis, and osteomalacia or renal rickets. The clinical spectrum of dRTA is broad; no single pathogenetic mechanism exists.

"Backleak" dRTA is due to Amphotericin B therapy in patients with hypokalemic dRTA.

Type 2 or Proximal RTA

Wikipedia. Proximal RTA (pRTA) is caused by a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. The distal intercalated cells function normally, so the acidemia is less severe than dRTA and the urine can acidify to a pH of less than 5.3. pRTA also has several causes, and may occasionally be present as a solitary defect, but is usually associated with a more generalised dysfunction of the proximal tubular cells called Fanconi's syndrome where there is also phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular proteinuria. The principal feature of Fanconi's syndrome is bone demineralization (osteomalacia or rickets) due to phosphate wasting.

WebMD. Proximal RTA can be divided in two categories, isolated bicarbonate wasting and generalized proximal tubule dysfunction (Fanconi's syndrome). Each type can be further divided according to whether it is accompanied by systemic or genetic disease.

Patients with proximal RTA generally have a plasma bicarbonate concentration more than 15 mmol/L; severe metabolic acidosis rarely develops. In fact, all the filtered bicarbonate will be completely reclaimed, and these patients will have normal distal nephron acidification. Thus, in patients with proximal RTA, urine is acidified normally during acidemia.

When plasma bicarbonate is raised by exogenous addition of alkali, the reduced proximal capacity to reabsorb bicarbonate leads to bicarbonaturia. After cessation of alkali administration, urinary bicarbonate wastage continues until the filtered load reaches the level at which the combined reabsorptive capacity of the proximal tubule and the distal tubule is no longer exceeded; urine bicarbonate concentration then becomes low and urine pH is appropriately acidic.

Isolated defects in proximal tubule bicarbonate reabsorption are rarely identified. Most patients with proximal RTA have multiple defects in proximal tubular function, including defective reabsorption of glucose, calcium, phosphate, citrate, uric acid, lysozymes, light-chain immunoglobulins, and amino acids.

Low serum potassium due to distal potassium wasting is a consistent finding in proximal RTA. This involves the renin-angiotensin-aldosterone system (RAAS). Kaliuresis is promoted by increased distal delivery of sodium bicarbonate and by hyperaldosteronism resulting from volume contraction. Plasma renin levels are typically elevated. The rate of kaliuresis is, therefore, proportional to the bicarbonate delivery to the distal nephron and also to the plasma bicarbonate concentration. Administration of alkali to correct acidosis in these patients leads to an exaggeration of the kaliuresis and potassium deficiency.

Patients with proximal RTA may have high urinary calcium excretion; however, nephrocalcinosis and renal calculi are rare. This may be due to the relatively normal rate of citrate excretion in these patients as compared with that of most acidotic patients.

Children with proximal RTA are likely to have growth retardation, rickets, osteomalacia, and abnormal vitamin D metabolism. In adults, osteopenia may develop but generally without pseudofractures.

Type 3 RTA - Combined proximal and distal RTA

Wikipedia. In some patients, their RTA shares features of both dRTA and pRTA. This rare pattern was observed in the 1960s and 1970s as a transient phenomenon in infants and children with dRTA, possibly in relation with some exogenous factor such as high salt intake, and is no longer observed. This form of RTA has also been referred to as juvenile RTA.

Combined dRTA and pRTA is also observed as the result of inherited carbonic anhydrase II deficiency. Mutations in the gene encoding this enzyme give rise to an autosomal recessive syndrome of osteopetrosis, renal tubular acidosis, cerebral calcification, and mental retardation. It is very rare and cases from all over the world have been reported, of which about 70% are from the Magreb region of North Africa, possibly due to the high prevalence of consanguinity there. The kidney problems are treated as described above. There is no treatment for the osteopetrosis or cerebral calcification.

Type 4 RTA or Hyperkalaemic RTA

Wikipedia. Type 4 RTA is due to either a deficiency of aldosterone, or to a resistance to its effects. Type 4 RTA is not actually a tubular disorder at all nor does it have a clinical syndrome similar to the other types of RTA described above. It was included in the classification of renal tubular acidoses as it is associated with a mild (normal anion gap) metabolic acidosis due to a physiological reduction in proximal tubular ammonium excretion, which is secondary to hypoaldosteronism, and results in a decrease in urine buffering capacity. Its cardinal feature is hyperkalemia, and measured urinary acidification is normal, hence it is often called hyperkalemic RTA or tubular hyperkalemia.

Causes include:
  • Aldosterone deficiency (hypoaldosteronism): Primary vs. hyporeninemic
  • Aldosterone resistance
  1. Drugs: Amiloride, Spironolactone, Trimethoprim, Pentamidine
  2. Pseudohypoaldosteronism

Sources:
RTA in Wikipedia
RTA in MedIndia
Distal RTA in WebMD
Proximal RTA in WebMD

Acid-base imbalance - questions (Q1)

Here are some answer guides. They are merely guides. You can read up own your own.
Prof Faridah

Q1. Alkalosis causes decrease in free calcium ions due to association with protein. But in milk-alkali syndrome, the alkaemia will cause an increase in renal absorption of calcium --> hypercalcemia...so..?
a) Is it alkalosis will cause decrease in calcium, provided only if the kidney is dysfunctional? So there is no reabsorption?
b) Does alkaemia and alkalosis have different effects on the calcium ions? If yes, how? Examples?

My response:
  1.  Calcium ion binding (association) and dissociation from albumin are reversible processes, and are dependent on blood pH. Acidosis favours calcium ion dissociation, while alkalosis favours calcium ion binding.
  2. Calcium levels in blood are determined in the clinical lab 2 ways, as Total calcium and as Ionised calcium. Total calcium is the sum of free Ionised calcium + Protein-bound calcium. Total calcium is a cheaper test to do than Ionised calcium. For most clinical labs, Total calcium will suffice. Rarely is Ionised calcium requested by doctors.
  3. Hypercalcemia prevails in alkalosis. This hypercalcemia is marked by high Total calcium levels but low Ionised calcium levels. This is because alkalosis itself favours binding of free Ionised calcium (Ca2+) to proteins, and the most abundant plasma protein is albumin. So, alkalosis favours binding of calcium ions to albumin, thus reducing the value for free Ionised calcium; Total calcium remains high.
  4. Previously, people were taking "milk of magnesia" as a remedy for dyspepsia (any stomach upset). Milk of magnesia is an alkaline preparation and an OTC substance (over the counter; means can be purchased without prescription). Of course people may have taken it in excess and for extended periods as usually stomach complaints don't usually go away that easily.
  5. When alkaline media is taken in large amounts and for extended periods, it can result in milk-alkali syndrome. If left untreated, milk-alkali syndrome may lead to metastatic calcification and renal failure. The kidneys is dysfunctional in renal failure. Since this condition is alkalosis, and the renal system is dysfunctional, excess bicarbonate and calcium are not excreted or are minimally excreted, if any. Thus, in milk-alkali syndrome with renal failure, we should see a severe alkalosis with hypercalcemia.
  6. Alkalosis refers to alkaline conditions within cells; alkalaemia refers to alkaline conditions within blood; both have pH>7 (by chemical definiton) (>pH7.4 by physiological definition).

Disorders of calcium metabolism

Disorders of calcium metabolism occur when the body has too little or too much calcium. The serum level of calcium is closely regulated within a fairly limited range in the human body.

The amount of biologically active calcium varies with the level of serum albumin, a protein to which calcium is bound, and therefore levels of ionized calcium are better measures than a total calcium; however, one can correct a total calcium if the albumin level is known.
  • A normal ionized calcium is 1.12-1.45 mmol/L (4.54-5.61 mg/dL).
  • A normal total calcium is 2.2-2.6 mmol/L (9-10.5 mg/dL).
    • Total calcium of less than 8.0 mg/dL is hypocalcaemia, with levels below 1.59 mmol/L (6 mg/dL) generally fatal.
    • Total calcium of more than 10.6 mg/dL is hypercalcaemia, with levels over 3.753 mmol/L (15.12 mg/dL) generally fatal.

Source: Wikipedia

Hypercalcemia

Definition

Hypercalcaemia (in American English, hypercalcemia) is an elevated calcium level in the blood. (Normal range: 9–10.5 mg/dL or 2.2–2.6 mmol/L). It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a workup should be undertaken if it persists. It can be due to excessive skeletal calcium release, increased intestinal calcium absorption, or decreased renal calcium excretion.

Signs and Symptoms 

There is a general mnemonic for remembering the effects of hypercalcaemia: "groans (constipation), moans (psychic moans (e.g., fatigue, lethargy, depression)), bones (bone pain, especially if PTH is elevated), stones (kidney stones), and psychiatric overtones (including depression and confusion)."

Other symptoms can include fatigue, anorexia, nausea, vomiting, pancreatitis and increased urination.

Abnormal heart rhythms can result, and ECG findings of a short QT interval and a widened T wave suggest hypercalcaemia. Significant hypercalcaemia can cause ECG changes mimicking an acute myocardial infarction.

Peptic ulcers may also occur.

Symptoms are more common at high blood calcium values (12.0 mg/dL or 3 mmol/L). Severe hypercalcaemia (above 15–16 mg/dL or 3.75–4 mmol/L) is considered a medical emergency: at these levels, coma and cardiac arrest can result.

Causes

Known causes can be grouped into 5 types: 1) Abnormal parathyroid gland function, 2) Malignancy, 3) Vitamin D metabolic disorders, 4) Disorders related to high bone-turnover rates, and 5) Renal failure.

Primary hyperparathyroidism and malignancy account for about 90% of cases of hypercalcaemia.

Abnormal parathyroid gland function

  • primary hyperparathyroidism (see Parathyroid in New World Encyclopedia)
    • solitary parathyroid adenoma
    • primary parathyroid hyperplasia
    • parathyroid carcinoma
    • multiple endocrine neoplasia (MEN)
    • familial isolated hyperparathyroidism
  • lithium use
  • familial hypocalciuric hypercalcaemia/familial benign hypercalcaemia
Malignancy
  • solid tumour with metastasis (e.g. breast cancer or classically squamous cell carcinoma, which can be PTHrP-mediated)
  • solid tumour with humoral mediation of hypercalcaemia (e.g. lung cancer [most commonly non-small cell lung cancer] or kidney cancer, phaeochromocytoma)
  • haematologic malignancy (multiple myeloma, lymphoma, leukaemia)
Vitamin D metabolic disorders
  • hypervitaminosis D (vitamin D intoxication)
  • elevated 1,25(OH)2D (see calcitriol under Vitamin D) levels (e.g. sarcoidosis and other granulomatous diseases)
  • idiopathic hypercalcaemia of infancy
  • rebound hypercalcaemia after rhabdomyolysis
Disorders related to high bone-turnover rates
  • hyperthyroidism
  • prolonged immobilization
  • thiazide use
  • vitamin A intoxication
  • Paget's disease of the bone
  • multiple myeloma
Renal failure
  • severe secondary hyperparathyroidism
  • aluminium intoxication
  • milk-alkali syndrome
Treatment

The goal of therapy is to treat the hypercalcaemia first and subsequently effort is directed to treat the underlying cause. Treating hypovolemia should come first and treatment is systematic, treat one thing at a time. Overtreating hypovolemia leads to edema.

There are 3 treatment modes: 1) Initial therapy (fluids and diuretics), 2) Additional therapy (bisphosphonates and calcitonin), and 3) Other therapies.

Initial therapy (fluids and diuretics)

Hydration, increasing salt intake, and forced diuresis.
  • hydration is needed because many patients are dehydrated due to vomiting or renal defects in concentrating urine.
  • increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion (In other words, calcium and sodium (salt) are handled in a similar way by the kidney. Anything that causes increased sodium (salt) excretion by the kidney will, en passant, cause increased calcium excretion by the kidney)
  • after rehydration, a loop diuretic such as furosemide can be given to permit continued large volume intravenous salt and water replacement while minimizing the risk of blood volume overload and pulmonary oedema. In addition, loop diuretics tend to depress renal calcium reabsorption thereby helping to lower blood calcium levels
  • can usually decrease serum calcium by 1–3 mg/dL within 24 h
  • caution must be taken to prevent potassium or magnesium depletion
Additional therapy (bisphosphonates and calcitonin)
  • bisphosphonates are pyrophosphate analogues with high affinity for bone, especially areas of high bone-turnover.
    • they are taken up by osteoclasts and inhibit osteoclastic bone resorption
    • current available drugs include (in order of potency): (1st gen) etidronate, (2nd gen) tiludronate, IV pamidronate, alendronate (3rd gen) zoledronate and risedronate
    • all patients with cancer-associated hypercalcaemia should receive treatment with bisphosphonates since the 'first line' therapy (above) cannot be continued indefinitely nor is it without risk. Further, even if the 'first line' therapy has been effective, it is a virtual certainty that the hypercalcaemia will recur in the patient with hypercalcaemia of malignancy. Use of bisphosphonates in such circumstances, then, becomes both therapeutic and preventative
    • patients in renal failure and hypercalcaemia should have a risk-benefit analysis before being given bisphosphonates, since they are relatively contraindicated in renal failure.
  • Calcitonin blocks bone resorption and also increases urinary calcium excretion by inhibiting renal calcium reabsorption
    • Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates
    • Helps prevent recurrence of hypercalcaemia
    • Dose is 4 Units per kg via subcutaneous or intramuscular route every 12 hours, usually not continued indefinitely
Other therapies

Rarely used, or used in special circumstances
  • plicamycin inhibits bone resorption (rarely used)
  • gallium nitrate inhibits bone resorption and changes structure of bone crystals (rarely used)
  • glucocorticoids increase urinary calcium excretion and decrease intestinal calcium absorption
    • no effect on calcium level in normal or primary hyperparathyroidism
    • effective in hypercalcaemia due to osteolytic malignancies (multiple myeloma, leukaemia, Hodgkin's lymphoma, carcinoma of the breast) due to antitumor properties
    • also effective in hypervitaminosis D and sarcoidosis
  • dialysis usually used in severe hypercalcaemia complicated by renal failure. Supplemental phosphate should be monitored and added if necessary
  • phosphate therapy can correct the hypophosphataemia in the face of hypercalcaemia and lower serum calcium
Emergency - Hypercalcaemic crisis

A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/L).

The main symptoms of a hypercalcaemic crisis are oliguria or anuria, as well as somnolence or coma.

After recognition, primary hyperparathyroidism should be proved or excluded.

In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death. The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium. Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin, as well as bisphosphonates (which have effect on calcium levels after one or two days).


Source: Wikipedia

Tuesday 4 October 2011

Calcium metabolism

Calcium metabolism or calcium homeostasis is the mechanism by which the body maintains adequate calcium levels. Derangements of this mechanism lead to hypercalcemia or hypocalcemia, both of which can have important consequences for health.

Calcium pool and distribution in the body

Wikipedia. Calcium is the most abundant mineral in the human body. The average adult body contains in total approximately 1 kg, 99% in the skeleton in the form of calcium phosphate salts. The extracellular fluid (ECF) contains approximately 22.5 mmol, of which about 9 mmol is in the serum. Approximately 500 mmol of calcium is exchanged between bone and the ECF over a period of twenty-four hours.

Medpedia. Calcium, the most abundant mineral in the human body, has several important functions. More than 99% of total body calcium is stored in the bones and teeth where it functions to support their structure. The remaining 1% is found throughout the body in blood, muscle, and the fluid between cells. Calcium is needed for muscle contraction, blood vessel contraction and expansion, the secretion of hormones and enzymes, and sending messages through the nervous system. A constant level of calcium is maintained in body fluid and tissues so that these vital body processes function efficiently.
Bone undergoes continuous remodeling, with constant resorption (breakdown of bone) and deposition of calcium into newly deposited bone (bone formation). The balance between bone resorption and deposition changes as people age. During childhood there is a higher amount of bone formation and less breakdown. In early and middle adulthood, these processes are relatively equal. In aging adults, particularly among postmenopausal women, bone breakdown exceeds its formation, resulting in bone loss, which increases the risk for osteoporosis (a disorder characterized by porous, weak bones).

Calcium absorption

Medpedia. Calcium is a naturally occurring mineral that is needed by the body to build and maintain strong bones and teeth, enable muscle contraction, facilitate chemical reactions in cells, regulate blood vessel size, and send messages through the nervous system. A constant level of calcium is maintained in body fluid and tissues so that these vital body processes function efficiently.
Because calcium is not made in the body, it must be absorbed from a person's dietary intake. Calcium is shed from the body in skin, nails, hair, sweat, urine, and feces. When a person does not get enough calcium through their diet, the body must break down bone to obtain the mineral.
Throughout life, bones go through a process known as remodeling, in which small amounts of old bone are removed and new bone is formed in its place. Generally, after age 35, more bone is lost than gained. Bone loss accelerates after menopause. Calcium from food or supplements is absorbed in the intestines. Vitamin D is necessary for this absorption. Some substances interfere with calcium absorption.

Calcium absorption refers to the amount of calcium that is absorbed from the digestive tract into the body's circulation. Calcium absorption can be affected by the calcium status of the body, vitamin D status, age, pregnancy and plant substances in the diet. The amount of calcium consumed at one time such as in a meal can also affect absorption. For example, the efficiency of calcium absorption decreases as the amount of calcium consumed at a meal increases.

Factors affecting calcium absorption

Age

Net calcium absorption can be as high as 60% in infants and young children, when the body needs calcium to build strong bones. Absorption slowly decreases to 15-20% in adulthood and even more as one ages. Because calcium absorption declines with age, recommendations for dietary intake of calcium are higher for adults ages 51 and over.

Vitamin D

Vitamin D is vital for efficient calcium absorption. Without sufficient vitamin D, the small intestine absorbs ~15% of dietary calcium, while with sufficient vitamin, the small intestine absorbs ~30% of dietary calcium. Calcium absorption during growth, lactation, and pregnancy can increase to 80% of dietary calcium. Vitamin D is a fat-soluble vitamin that is obtained either from food or it can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation. When exposure to UVB radiation is insufficient for the synthesis of adequate amounts of vitamin D in the skin, adequate intake of vitamin D from the diet is essential for health. The Office of Dietary Supplement's vitamin D fact sheet provides more information.

Pregnancy

Current calcium recommendations for nonpregnant women are also sufficient for pregnant women because intestinal calcium absorption increases during pregnancy. For this reason, the calcium recommendations established for pregnant women are not different than the recommendations for women who are not pregnant.

Foods

Phytic acid and oxalic acid, which are found naturally in some plants, and thus foods, may bind to calcium and prevent it from being absorbed optimally. These substances affect the absorption of calcium from the plant itself, not the calcium found in other calcium-containing foods eaten at the same time. Examples of foods high in oxalic acid are spinach, collard greens, sweet potatoes, rhubarb, and beans. Foods high in phytic acid include whole grain bread, beans, seeds, nuts, grains, and soy isolates. Although soybeans are high in phytic acid, the calcium present in soybeans is still partially absorbed. Fiber, particularly from wheat bran, could also prevent calcium absorption because of its content of phytate. However, the effect of fiber on calcium absorption is more of a concern for individuals with low calcium intakes. The average American tends to consume much less fiber per day than the level that would be needed to affect calcium absorption.

Wikipedia. About 25 mmol of calcium enters the body in a normal diet. Of this, about 40% (10 mmol) is absorbed in small intestine, and 5 mmol leaves the body in feces, netting 5 mmol of calcium a day. Calcium is absorbed across the intestinal brush border membrane, passing through ion channels such as TRPV6. Calbindin is a vitamin D-dependent calcium-binding protein inside intestinal epithelial cells which functions together with TRPV6 and calcium pumps (PMCA1) in the basal membrane to actively transport calcium into the body. The active transport occurs primarily in the duodenum when calcium intake is low, and passive paracellular diffusion occurs in the ileum and jejunum, independent of Vitamin D, when calcium intake is high.

Calcium excretion

Wikipedia. The kidney excretes 250 mmol a day in pro-urine, and resorbs 245 mmol, leading to a net loss in the urine of 5 mmol/d. In addition to this, the kidney processes Vitamin D into calcitriol, the active form that is most effective in assisting intestinal absorption. Both processes are stimulated by parathyroid hormone. 

This refers to the amount of calcium eliminated from the body in urine, feces and sweat. Calcium excretion can be affected by many factors including dietary sodium, protein, caffeine and potassium.

Factors affecting calcium excretion

Sodium and protein

Typically, dietary sodium and protein increase calcium excretion as the amount of their intake is increased. However, if a high protein, high sodium food also contains calcium, this may help counteract the loss of calcium.

Potassium

Increasing dietary potassium intake (such as from 7-8 servings of fruits and vegetables per day) in the presence of a high sodium diet (>5100 mg/day, which is more than twice the Tolerable Upper Intake Level of 2300 mg for sodium per day) may help decrease calcium excretion particularly in postmenopausal women.

Caffeine

Caffeine has a small effect on calcium absorption. It can temporarily increase calcium excretion and may modestly decrease calcium absorption, an effect easily offset by increasing calcium consumption in the diet. One cup of regular brewed coffee causes a loss of only 2-3 mg of calcium easily offset by adding a tablespoon of milk. Moderate caffeine consumption (1 cup of coffee or 2 cups of tea per day) in young women who have adequate calcium intakes has little to no negative effects on their bones.

Other factors

  • Phosphorus: The effect of dietary phosphorus on calcium is minimal. Some researchers speculate that the detrimental effects of consuming foods high in phosphate such as carbonated soft drinks is due to the replacement of milk with soda rather than the phosphate level itself.
  • Alcohol: Alcohol can affect calcium status by reducing the intestinal absorption of calcium. It can also inhibit enzymes in the liver that help convert vitamin D to its active form which in turn reduces calcium absorption. However, the amount of alcohol required to affect calcium absorption is unknown. Evidence is currently conflicting whether moderate alcohol consumption is helpful or harmful to bone.
In summary, a variety of factors that may cause a decrease in calcium absorption and/or increase in calcium excretion may negatively affect bone health.

Normal calcium levels in blood/serum

Total calcium comprises protein-bound calcium and free calcium ions in blood plasma (measured as serum calcium). Free calcium ions mean (refer to) ionized calcium which are not bound to plasma proteins.

The serum level of calcium is closely regulated with a normal total calcium of 2.2-2.6 mmol/L (9-10.5 mg/dL) and a normal ionized calcium of 1.1-1.4 mmol/L (4.5-5.6 mg/dL).

The amount of total calcium varies with the level of serum albumin, a protein to which calcium is bound.

The biologic effect of calcium is determined by the amount of ionized calcium, rather than the total calcium.

Ionized calcium does not vary with the albumin level, and therefore it is useful to measure the ionized calcium level when the serum albumin is not within normal ranges, or when a calcium disorder is suspected despite a normal total calcium level.

Corrected calcium level

Serum is preferred for blood biochemistry determinations. These blood analytes are determined using serum: serum total calcium, serum albumin.  

Corrected calcium is determined using a formula. Calcium exists in 2 states in the body - bound to protein (mostly albumin) and free ionized calcium. Total calcium is the sum of protein-bound calcium plus free ionized calcium.


(i) Determination of calcium when albumin level is abnormal

One can derive a corrected calcium level when the albumin level is abnormal. This is to make up for the change in total calcium due to the change in albumin-bound calcium, and gives an estimate of what the calcium level would be if the albumin were within normal ranges.
Corrected calcium (mg/dL) = measured total calcium (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]), where 4.0 represents the average albumin level in g/dL.
In other words, each 1 g/dL decrease of albumin will decrease 0.8 mg/dL in measured serum calcium and thus 0.8 must be added to the measured Calcium to get a corrected Calcium value.
Or: Corrected calcium (mmol/L) = measured total calcium (mmol/L) + 0.02 (40 - serum albumin [g/L]), where 40 represents the average albumin level in g/L
In other words, each 1 g/L decrease of albumin, will decrease 0.02 mmol/L in measured serum calcium and thus 0.02 must be added to the measured value to take this into account and get a corrected calcium.

(ii) Determination of calcium when albumin level is low

When there is hypoalbuminemia (a lower than normal albumin), the corrected calcium level is higher than the total calcium. 

The role of bone

Although calcium flow to and from the bone is neutral, about 5 mmol is turned over a day. Bone serves as an important storage point for calcium, as it contains 99% of the total body calcium. Calcium release from bone is regulated by parathyroid hormone. Calcitonin stimulates incorporation of calcium in bone, although this process is largely independent of calcitonin.

Low calcium intake may also be a risk factor in the development of osteoporosis. In one meta-analysis, the authors found that fifty out of the fifty-two studies that they reviewed showed that calcium intake promoted better bone balance. With a better bone balance, the risk of osteoporosis is lowered.


Sources:
Calcium metabolism in Wikipedia
Calcium in Medpedia