Disorders of liver and kidney – Jaundice, fatty liver, normal and abnormal functions of liver and kidney. Inulin and urea clearance. Abnormalities of nitrogen metabolism

1. Disorders of liver and kidney
Jaundice
• It is most common known disease of bilirubin
metabolism in which skin and sclera of eye acquires
yellow color due to excessive bilirubin in blood.
• Normal blood plasma bilirubin level is 1 mg/dl. In
jaundice the plasma bilirubin level is high.
• Hence excess bilirubin diffuses into tissues and turns
them yellow. Further, excess bilirubin leads to a condition
known as hyper bilirubinemia.
Dr. Shiny C Thomas, Department of Biosciences, ADBU

2. • Thus the characteristic signs of jaundice are
hyperbilirubinemia and yellow colored skin and sclera.
• Based on clinical causes jaundice is classified into pre
hepatic jaundice, hepatic jaundice and post hepatic
jaundice.
• However jaundice (Icterus) may be due to several
underlying diseases.

3. Pre hepatic or hemolytic jaundice
• It is due to excessive breakdown of erythrocytes. This
leads to increased production of bilirubin.
• But liver cells are unable to conjugate all bilirubin formed.
Hence unconjugatedbilirubin level of plasma is elevated.
• Excessive breakdown of RBC occurs in
hemglobinopathies, hereditary spherocytosis,
incompatible blood transfusion and in malaria.
• Administration of sulfonamides, aspirin and primaquine
can cause excessive breakdown of RBC in glucose-6-
phosphate dehydrogenase deficiency.

4. Hepatic or hepatocellular jaundice
• It is due to damaged hepatocytes. Poisons like
chloroform, carbon tetrachloride, phosphorus,
antibiotics, amanita mushroom poison and hepatitis virus
can damage parenchymal cells of liver. In cirrhosis also
liver cell damage occurs.
• Damaged hepatocytes are unable to perform functions.
So in hepatic jaundice liver cells are unable to conjugate or
secrete bilirubin though the production of bilirubin is as
usual.
• If conjugation of bilirubin is impaired unconjugated
bilirubin in plasma is elevated .

5. • If secretion of conjugated bilirubin is impaired
conjugated bilirubin in plasma is elevated.
• Therefore in hepatic jaundice appreciable amounts of
conjugated as well as unconjugated bilirubin are present
in plasma.
Post hepatic or obstructive jaundice
• It is due to obstruction of bile duct.
• Gall stones and cancer of head of pancreas can cause
obstruction of bile duct.
• Due to blockage of bile duct conjugated bilirubin
secreted by liver returns to blood.
• Hence in obstructive jaundice conjugated bilirubin in
plasma is elevated.
Cholestatic jaundice is term used to indicate all forms of
extrahepatic or post hepatic obstructive jaundice.

6. Intestinal metabolism of bilirubin

8. Vanden Bergh reaction and Jaundice
• Since bilirubin level is elevated in all forms of jaundice
measurement of serum bilirubin is useful in the diagnosis
and management of jaundice.
• Vanden Bergh devised a method based on Ehrlichs
reaction for measurement of bilirubin in plasma. It
involves coupling of diazotized sulphanilic acid (diazo
reagent) and bilirubin to produce a reddish purple azo
compound.
• It consists of two parts (a) Direct Vanden Bergh reaction
and (b) Indirect Vanden Bergh reaction.

9. Urine bilirubin in Jaundice
• Normal urine does not contain bilirubin because normal blood
contains water insoluble unconjugated bilirubin which can not be
filtered at glomerulus.
• Bilirubin is excreted in urine in hepatic and obstructive jaundice
because conjugated bilirubin level in plasma is above renal
threshold value in these conditions.
• (Obstructive jaundice is a specific type of jaundice where symptoms develop
due to a narrowed or blocked bile duct or pancreatic duct, preventing the
normal drainage of bile from the bloodstream into the intestines)
• However bilirubin is absent in urine in hemolytic jaundice.
Excretion of bilirubin urine is called as choluria.
• So hepatic and obstructive jaundice are called as choluric jaundice
where as hemolytic jaundice is called as acholuric jaundice.

10. Urine Urobilinogen in Jaundice
• About 4 mg of urobilinogen is excreted in urine per day.
• The excretion of urobilinogen depends on amount of
bilirubin entering intestine which in turn depends on
amount of bilirubin formed.
• In obstructive jaundice urobilinogen is not found in urine
because bilirubin can not enter intestine.
• In hemolytic jaundice urine urobilinogen is more
because of increased production of bilirubin.
Urine bilirubin and Urobilinogen in Jaundice
Combination of urine bilirubin and urobilinogen is useful in
differential diagnosis of jaundice.

11. Urobilinogen is a colorless by-product of bilirubin reduction.
• It is formed in the intestines by bacterial action on
bilirubin. About half of the urobilinogen formed is
reabsorbed and taken up via the portal vein to the liver,
enters circulation and is excreted by the kidney.
• Increased amounts of bilirubin are formed in hemolysis,
which generates increased urobilinogen in the gut.
• In liver disease (such as hepatitis), the intrahepatic
urobilinogen cycle is inhibited also increasing
urobilinogen levels.
• Urobilinogen is converted to the yellow
pigmented urobilin apparent in urine

12. Fatty livers
1. Liver contains about 5% lipid. Of this, about 1/4 is
triglyceride.
2. Extensive accumulation of lipid in the liver leads to
condition known as fatty liver. In the fatty livers, the lipid
content increases to 25-30%. Further, triglycerides and fatty
acid may occupy entire cytoplasm of hepatocyte.
• Presence of bilirubin in urine without urobilinogen
suggests obstructive jaundice.
• Absence of bilirubin in urine with increased urobilinogen
suggest hemolytic jaundice.

13. Several factors causes accumulation of lipid in liver
1. Raised plasma free fatty acid level
• When there is a mobilization of fat from adipose and
extrahepatic tissues plasma free fatty acid level
increases. Liver takes up increasing amounts of fatty
acids and esterifies them.
• Hence rate of triglyceride synthesis is more.
• However, the synthesis of VLDL occurs only at normal
rate. As a result triglycerides accumulate and cause fatty
liver.
• The plasma free fatty acid level is elevated in (a)
starvation (b) diabetes (c) high fat diet (d) carnitine
deficiency. Hence, in these conditions fatty liver occurs.

14. Carnitine is the generic term for a number of compounds that include L-carnitine,
acetyl-L-carnitine, and propionyl-L-carnitine [1,2]. Carnitine plays a critical role in
energy production. It transports long-chain fatty acids into the mitochondria so they
can be oxidized ("burned") to produce energy

15. 2. Metabolic block in the production of lipoproteins
• Block in VLDL formation causes fatty liver even though
the rate of triglyceride synthesis is normal because VLDL
transports triglyceride from liver to extra hepatic tissues.
• VLDL formation may be blocked if substance (s) required
for its formation are deficient. However, when deficient
substances are supplied fat accumulation cease.

16. 3. Lipotropic factors
• They are compounds that relieve or prevent excess
accumulation of lipids in the liver. They are choline,
methionine and betaine.
• These lipotropic factors cure fatty liver due to choline or
methionine deficiency. Choline deficiency may result
from impaired transmethylation reactions associated
with methionine catabolism.
• Choline deficiency leads to block in choline dependent
phospholipid biosynthesis. This in turn impairs formation
of membranes needed for lipoprotein synthesis.

17. • Thus choline deficiency results in block in VLDL
formation and causes accumulation of fat in liver.
• Other noteworthy lipotropic factors are PUFA, vit E,
pyridoxine and pantothenic acid.
• The deficiency of any one of these substances causes
fatty liver. However, they can not prevent occurrence of
fatty liver due to choline deficiency.

18. 4. Toxic substances
• Several hepato toxic agents like carbon tetrachloride,
chloroform, phosphorus, lead, arsenic, alcohol and orotic
acid causes fatty liver.
• Substances, which inhibit protein synthesis like puromycin
and ethionine, a methionine analog also cause fatty liver.
Medical Importance
Effect of fatty liver When accumulation of lipid in liver
becomes chronic fibrotic changes takes place in hepatocytes,
which progress to cirrhosis and finally impaired liver function.

19. Functions of liver
1. Liver is an essential organ. It has diverse functions.
2. Liver is involved in secretion or excretion of several
components like bilirubin and bile
acids.
3. It is involved in the synthesis of plasma proteins and
blood clotting factors.
4. It is involved in metabolism of carbohydrates, lipids and
proteins.
5. It is sensitive to actions of several hormones.
6. It is involved in xenobiotics metabolism.

20. Functions of Kidney
1. Kidney is an essential organ. It has several diverse
functions.
2. Nephron is functional unit of kidney. It consists of
glomerulus and renal tubules
3. Kidney maintains water, electrolyte and acid base balance
of the body through filtration and reabsorption process.
Glomerulus is responsible for filtration and renal tubules are
involved in reabsorption. In addition renal tubules secretes
some solute molecules.
4. Kidney clears several non-protein metabolic waste products
like urea, uric acid, creatinine etc., from circulation.
5. Kidney produces erythropoietin, calcitriol, renin and
prostaglandins.

21. Since glomerulus and renal tubules are major functional
units of kidney most of the kidney function tests done to
assess renal damage are based on either function of
glomerulus or renal tubules.

22. Inulins and Urea clearance
• Inulin are a group of naturally occurring polysaccharides produced
by many types of plants, industrially most often extracted
from chicory.
• The inulins belong to a class of dietary fibers known as fructans.
Inulin is used by some plants as a means of storing energy and is
typically found in roots or rhizomes.
• Most plants that synthesize and store inulin do not store other
forms of carbohydrate such as starch. I
• n the United States in 2018, the Food and Drug
Administration approved inulin as a dietary fiber ingredient used to
improve the nutritional value of manufactured food products.
• Using inulin to measure kidney function is the "gold standard" for
comparison with other means of estimating glomerular filtration
rate.

23. Abnormalities of Nitrogen metabolism
Uraemia
It is the condition of a raised plasma urea concentration and
is almost always accompanied by an elevated creatinine
concentration.
Urea is derived in the liver from amino acids and from
protein, either from the diet or from tissues.
The normal kidney can excrete large amounts of urea. If the
rate of production exceeds the rate of clearance, plasma
concentrations rise.

24. The rate of production is accelerated by:
• a high-protein diet,
• absorption of amino acids and peptides from digested
blood
• increased catabolism due to starvation, tissue damage,
sepsis or steroid treatment.
• Renal failure- causes retention of water and salt

25. Effects of Renal Failure on the
Body Fluids—Uremia
The effect of complete renal
failure on the body fluids
depends on (1) water and food
intake and (2) the degree of
impairment of renal function.
Assuming that a person with
complete renal failure
continues to ingest the same
amounts of water and food, the
concentrations of different
substances in the extracellular
fluid are approximately those
shown in Figure.

26. Important effects include
(1) generalized edema resulting from water and salt
retention,
(2) acidosis resulting from failure of the kidneys to rid the
body of normal acidic products,
(3) high concentration of the nonprotein nitrogens—
especially urea, creatinine, and uric acid—resulting from
failure of the body to excrete the metabolic
end products of proteins, and
(4) high concentrations of other substances excreted by the
kidney, including phenols, sulfates, phosphates, potassium,
and guanidine bases.
This total condition is called uremia because of the high
concentration of urea in the body fluids.

27. Hyperuricemia is an excess of uric acid in the blood. Uric
acid passes through the liver, and enters your bloodstream.
Most of it is excreted (removed from your body) in your
urine, or passes through your intestines to regulate
"normal" levels.
Normal Uric acid levels are 2.4-6.0 mg/dL (female) and 3.4-
7.0 mg/dL (male). Normal values will vary from laboratory
to laboratory.
Also important to blood uric acid levels are purines. Purines
are nitrogen-containing compounds, which are made inside
the cells of your body (endogenous), or come from outside
of your body, from foods containing purine (exogenous).

28. Purine breaks down into uric acid. Increased levels of uric
acid from excess purines may accumulate in your tissues,
and form crystals. This may cause high uric acid levels in the
blood.
Uric acid formation may occur when the blood uric acid
level rises above 7 mg/dL. Problems, such as kidney stones,
and gout (collection of uric acid crystals in the joints,
especially in your toes and fingers), may occur.
What causes hyperuricemia?
Causes of high uric acid levels (hyperuricemia) can be
primary (increased uric acid levels due to purine), and
secondary (high uric acid levels due to another disease or
condition). Sometimes, the body produces more uric acid
than it is able to excrete.

29. Causes of high uric acid levels include:
Primary hyperuricemia
Increased production of uric acid from purine
Your kidneys cannot get rid of the uric acid in your
blood, resulting in high levels
Secondary hyperuricemia
• Certain cancers, or chemotherapy agents may cause an
increased turnover rate of cell death.

30. • Kidney disease - not be able to clear the uric acid out
of body system, thus causing hyperuricemia.
• Medications - can cause increased levels of uric acid in
the blood
• Endocrine or metabolic conditions -certain forms of
diabetes, or acidosis can cause hyperuricemia
• Elevated uric acid levels may produce kidney problems

31. What are some symptoms of hyperuricemia to look for?
• kidney problems, or
• gouty arthritis (an inflammation of a joint (called "gout")
• fever, chills, fatigue if you have certain forms of cancer,
and your uric acid levels are elevated (caused by tumor
lysis syndrome)
• You may have kidney problems (caused by formation of
kidney stones), or problems with urination

32. Porphyria a rare hereditary disease in which there is
abnormal metabolism of the blood pigment haemoglobin.
Porphyrins are excreted in the urine, which becomes dark;
other symptoms include mental disturbances and extreme
sensitivity of the skin to light.
Porphyria is a group of rare diseases in which chemical
substances called porphyrins accumulate, leading to either
skin changes or neurological symptoms or sometimes both.

33. • The body requires porphyrins to produce heme, which
carries oxygen in the blood, but in the porphyrias there is
a deficiency (inherited or acquired) of the enzymes that
transform the various porphyrins into others, leading to
abnormally high levels of one or more of these
substances.

34. Porphyrias are classified in two ways, by symptoms and by
pathophysiology. Symptomatically,
(1) acute porphyrias primarily cause brain and nerve
involvement, often with severe abdominal
pain, vomiting, neuropathy, and mental disturbances.
(2) Cutaneous porphyrias cause skin problems, often after
exposure to sunlight, because porphyrins react with light.
Physiologically, porphyrias are classified as hepatic or
erythropoietic based on the sites of accumulation
of heme precursors, either in the liver or in the bone
marrow and red blood cells.

35. Change in urine color before and after sun exposure Left
figure is urine of the first day. Right figure is urine after sun
exposure for 3 days. Urine color changed to “port wine”
color after sun exposure.

36. • Skin disease is encountered where excess porphyrins
accumulate in the skin.
• Porphyrins are photoactive molecules, and exposure to
light results in promotion of electrons to higher energy
levels.
• When these return to the resting energy level or ground
state, energy is released. This accounts for the property
of fluorescence typical of the porphyrins. This causes
local skin damage.

37. Nitrogen Balance
• Nitrogen is a main body component and is required for
both tissue protein synthesis and the production of
several nitrogenous compounds involved in a variety of
functions (hormones, immune mediators,
neurotransmitters, antioxidant defences, etc.).
• Thus, the body nitrogen content should be both
quantitatively and qualitatively normal, as well as
normally maintained, to ensure normal body functions.

38. Nitrogen balance is a measure of nitrogen input minus
nitrogen output.
Nitrogen Balance = Nitrogen intake - Nitrogen loss
Sources of nitrogen intake include meat, dairy, eggs, nuts
and legumes, and grains and cereals.
Examples of nitrogen losses include urine, faeces, sweat,
hair, and skin.
Blood urea nitrogen can be used in estimating nitrogen
balance, as can the urea concentration in urine.
Nitrogen is a fundamental component of amino acids, which
are the molecular building blocks of protein. Therefore,
measuring nitrogen inputs and losses can be used to study
protein metabolism.

39. Positive nitrogen balance is associated with periods of
growth, hypothyroidism, tissue repair, and pregnancy.
This means that the intake of nitrogen into the body is
greater than the loss of nitrogen from the body, so there is an
increase in the total body pool of protein.
Negative nitrogen balance is associated with burns, serious
tissue injuries, fevers, hyperthyroidism, wasting diseases, and
during periods of fasting.
This means that the amount of nitrogen excreted from the
body is greater than the amount of nitrogen ingested.
A negative nitrogen balance can be used as part of a clinical
evaluation of malnutrition.

40. • Nitrogen balance is the traditional method of
determining dietary protein requirements.
• Determining dietary protein requirements using nitrogen
balance requires that all nitrogen inputs and losses are
carefully collected, to ensure that all nitrogen exchange is
accounted for.
• In order to control nitrogen inputs and losses, nitrogen
balance studies usually require participants to eat very
specific diets (so total nitrogen intake is known) and stay
in the study location for the duration of the study (to
collect all nitrogen losses).
• Because of these conditions, it can be difficult to study
the dietary protein requirements of certain populations
using the nitrogen balance technique (e.g. children).

41. Nitrogen Balance
Since protein is the main source of nitrogen in body the
dietary protein must make up nitrogen lost from body to
maintain nitrogen balance.
If an individuals total nitrogen content of the urine and
faeces equals the amount of dietary nitrogen then the
individual is said to be in nitrogen balance or equilibrium
Faecal nitrogen (N) + Urinary nitrogen (N) = Dietary nitrogen
(N)
N output = N intake
i.e.,
N intake
-------------- =1
N output

42. In other words if the ratio of nitrogen intake to nitrogen
output is one then the individual is in nitrogen balance or
equilibrium.

43. Positive nitrogen balance
• If the ratio of N intake to N output is greater than one
then it is called as positive nitrogen balance or if the N
output is less than N intake then the individual is in
positive nitrogen balance.
• In the positive nitrogen balance most of dietary nitrogen
is retained in the body and less is eliminated from body.
• More over in positive nitrogen balance the tissue protein
content increases due to increased protein synthesis.
• Usually it occurs during growth, pregnancy, lactation and
post operative recovery.

44. Negative nitrogen balance
• If the nitrogen output is more than the N intake then the
individual is in negative nitrogen balance or if the ratio of
N intake to N output is less than one then the individual is
in negative nitrogen balance.
• In the negative nitrogen balance nitrogen lost is not
replaced by dietary nitrogen. It occurs in malnutrition and
starvation, uncontrolled diabetes mellitus and cancer.
• Menstruating women may have transient negative
nitrogen balance if proper replacement for nitrogen lost is
not possible.
• Physical exercise trainee may also have transient negative
nitrogen balance because of atrophy of muscle.

45. Protein minimum
It is the minimum amount of dietary protein required to
maintain nitrogen balance.
It is 1 gm/kg body weight per day.
However protein requirement also depends on the (a)
Protein quality (b) Carbohydrate and fat contents (c) Physical
activity.
Protein quality
• Essential amino acid content determines quality of a
protein.
• An ideal or a good quality protein is the one which has
amino acid composition of body protein synthesized at
any given time.
• Further an ideal protein must meet essential amino acid
requirement.

46. Carbohydrate and fat content
• If diet contains sufficient amounts of carbohydrate and
fat then use of protein for energy production is reduced.
• Hence protein requirement in diet is minimum.
• In contrast if the diet contains inadequate amounts of
carbohydrates and fats then use of protein for energy
production is more. This increases protein requirement in
diet.
Physical activity
Protein requirement increases with increases in physical
activity due to retention of nitrogen or increased muscle
protein in the body.

47. • If a protein is unable to maintain nitrogen balance then it
is a poor quality protein.
• However nitrogen balance does not indicate anything
about digestibility, essential amino acid content and
assimilation of products of digestion.
• Usually good quality protein maintain nitrogen balance if
taken in adequate amounts.

48. Nitrogen Balance:
A healthy adult eating a varied and plentiful diet is generally
in “Normal Nitrogen Balance” a state where the amount of
nitrogen ingested each day is balanced by the amount
excreted resulting no net change in the amount of the body
Nitrogen. In a well fed condition, excreted nitrogen comes
from digestion of excess protein or from normal turnover.
Protein turnover (Synthesis and degradation)
Under some conditions. The body is either in negative or
positive nitrogen balance. In negative nitrogen balance more
nitrogen is excreted than ingested. This occurs in starvation
and certain diseases.

49. During starvation the carbon skeleton of most amino acids
from proteins fed in to gluconeogenesis to maintain the
blood glucose level ; in this process ammonia is released and
excreted mostly as urea and is not reincorporated in to
protein.
Positive nitrogen balance occurs in pregnancy and during
feeding after starvation.
A diet deficient in an essential amino acid also leads to a
negative nitrogen balance since body proteins are degraded
to provide the deficient essential amino acid.
Positive nitrogen balance occurs in growing children who are
increasing their body weight and incorporating more amino
acids in to protein than they breakdown.

50. Cysteine and Arginine are not essential in adults but
essential in children because they are synthesized from
Methionine and ornithine. These amino acids are readily
available in adults but limited in children.
Negative Nitrogen balance occurs in injury when there is net
destruction of tissue and in major trauma or illness.