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Alcohol induced Metabolic Alcohol induced Metabolic AlterationsAlterations
Namrata Chhabra, M.D.
1Namrata Chhabra, M.D.Biochemistry
AlcoholAlcohol
Everything comes at a price
2Namrata Chhabra, M.D.Biochemistry
3Namrata Chhabra, M.D.Biochemistry
Major pathway of Alcohol metabolism
4Namrata Chhabra, M.D.Biochemistry
Products of Alcohol Metabolism
5Namrata Chhabra, M.D.Biochemistry
Case details
• A 60 year old man was brought to hospital in a very serious condition.
• The patient complained of o Constant vomiting containing several hundred
mL of dark brown fluid from the previous two days plus
o Several episodes of melaena.
6Namrata Chhabra, M.D.Biochemistry
Past History
• Past history of alcoholism, cirrhosis, portal hypertension and a previous episode of bleeding varices was there.
• Sclerotherapy for the varices had been performed several months earlier at another hospital.
7Namrata Chhabra, M.D.Biochemistry
Examination
• The patient had jaundice and was in distress, sweaty, clammy and tachypnoeic.
• BP 98/50 mmHg, pulse 120/min. • Heart sounds - systolic murmur.• Peripheries were cold. • Abdomen was soft and non tender. • Signs of chronic liver disease were present (spider
naevi, gynecomastia, and testicular atrophy).
8Namrata Chhabra, M.D.Biochemistry
Laboratory Findings
Test Result Reference1) Blood glucose-50mg/dl 65-110 mg/dL2) Lactate 20.3 mmol/L 0.44- 1.8mmol/L3) Urea Nitrogen- 38.6mg/dl 8-25 mg/dL4) Creatinine- 1.24mg/dl 0.7-1.5mg/dL5) Uric acid- 9.8 mg/dL 3-7 mg/dL6) Blood alcohol -550 mg/dl No alcohol
9Namrata Chhabra, M.D.Biochemistry
Laboratory findings (contd.)
Test Result Reference7) Na+ 131 mmol/l 136-145 mmol/l.8) Cl- 85 mmol/l 96-106 mmol/l.9) K+ 4.2 mmol/l 3.5-5.5 mmol/L10) HCO3- 14.1 mmol/l 22-28 mmol/l.
10Namrata Chhabra, M.D.Biochemistry
Laboratory findings (contd.)
Test Result Reference11) pH 7.21 7.35-7.4512) pCO2 13.8 mmHg 35-45 mm
Hg13) pO2 103 mmHg 80-100 mm Hg
14) Hb 6.2 G/dL 14-18 G/dL 15) W.B.C. count 18 x103/mm3 5-10/ mm3
11Namrata Chhabra, M.D.Biochemistry
What is your
diagnosis ?
12Namrata Chhabra, M.D.Biochemistry
• The patient has multiple problems• Circulatory failure• GI bleeding on a background of known
Cirrhosis with Portal hypertension• Many other ??
Some Hints???
13Namrata Chhabra, M.D.Biochemistry
Some more hints ??
The patient has• Low Blood glucose (Hypoglycemia)• High Lactate• High Uric acid, BUN and creatinine• Electrolyte imbalance• Acid Base imbalance• Low Hb and high W.B.C. Count
14Namrata Chhabra, M.D.Biochemistry
15Namrata Chhabra, M.D.Biochemistry
• The blood glucose level in this patient is 50 mg/dL, well below the normal range of 65-110 mg/dL.Let’s find out the cause
16Namrata Chhabra, M.D.Biochemistry
17
Hypoglycemia results from an imbalance between demand and supply of glucose
Namrata Chhabra, M.D.Biochemistry
Which of the following conditions best explains the underlying cause of hypoglycemia in this
patient?
A. Impaired activity of Glycogen phosphorylaseB. Impaired activity of Glucose-6-PhosphataseC. Impaired activity of Pyruvate KinaseD. Reduced availability of substrates of
Gluconeogenesis
18Namrata Chhabra, M.D.Biochemistry
A) Impaired activity of Glycogen phosphorylase?
19Namrata Chhabra, M.D.Biochemistry
B) Impaired activity of Glucose-6-Phosphatase ?
20Namrata Chhabra, M.D.Biochemistry
C)Impaired activity of Pyruvate kinase?
21Namrata Chhabra, M.D.Biochemistry
D)Reduced availability of substrates of gluconeogenesis
22Namrata Chhabra, M.D.Biochemistry
23Namrata Chhabra, M.D.Biochemistry
Alcohol metabolism affects availability of substrates of
gluconeogenesis
24Namrata Chhabra, M.D.Biochemistry
25Namrata Chhabra, M.D.Biochemistry
Correct answer is -D
26Namrata Chhabra, M.D.Biochemistry
27Namrata Chhabra, M.D.Biochemistry
28Namrata Chhabra, M.D.Biochemistry
2) What is the cause of Lactic Acidosis in this patient ?
A. Reversal of reaction catalyzed by lactate dehydrogenase
B. Impaired activity of PDH complexC. Suppressed TCA cycleD. All of the above.
29Namrata Chhabra, M.D.Biochemistry
A) Reversal of reaction caused by Lactate dehydrogenase?
Pyruvate is converted to lactate to regenerate NAD +.
30Namrata Chhabra, M.D.Biochemistry
B) Impaired activity of PDH complex ?
31Namrata Chhabra, M.D.Biochemistry
C) Suppressed activities of TCA cycle enzymes?
TCA cycle
32Namrata Chhabra, M.D.Biochemistry
33Namrata Chhabra, M.D.Biochemistry
34
The correct answer is D
Namrata Chhabra, M.D.Biochemistry
35Namrata Chhabra, M.D.Biochemistry
• The very low pH indicates a severe acidosis. • The combination of a low pCO2 and low
bicarbonate indicates that it is metabolic acidosis.
36Namrata Chhabra, M.D.Biochemistry
Determination of Acid base status
pH H+ P CO2 HCO3-
Normal 7.4 40 mEq/L 40mm Hg 24 mEq/L
Respiratory acidosis
Respiratory Alkalosis
Metabolic acidosis
Metabolic Alkalosis
ROME
37Namrata Chhabra, M.D.Biochemistry
A.G
Cl- mEq/L
A.G
Cl- mEq/L
Na+
mEq/L Na+
mEq/LNa+
mEq/L
A.G
HCO3-
mEq/L HCO3-
mEq/L
HCO3-
mEq/L
Cl- mEq/L
A B C
A- Normal Ion DistributionB- High anion gap metabolic acidosisC- Normal anion gap acidosis
Anion Gap38Namrata Chhabra, M.D.Biochemistry
Normal or high anion gap metabolic acidosis ?
• The anion gap is 42 indicating the presence of a high anion gap disorder.
• The lactate level of 20.3mmol/l is extremely high and this is responsible for causing high anion gap.
39Namrata Chhabra, M.D.Biochemistry
High anion gap acidosis
• High anion gap is also there due to underlying Ketoacidosis.
• Acetyl co A fails to get utilized in TCA cycle, and the excess is channeled towards alternative pathways.
40Namrata Chhabra, M.D.Biochemistry
41Namrata Chhabra, M.D.Biochemistry
• Gouty arthritis is a common finding in chronic alcoholics
• Gout results from an increased body pool of urate with hyperuricemia.
• It is typically characterized by episodic acute and chronic arthritis, due to deposition of Mono sodium urate crystals in and around joints.
42Namrata Chhabra, M.D.Biochemistry
43Namrata Chhabra, M.D.Biochemistry
• In the given patient, serum uric acid concentration is higher than normal (9.8 mg/dL).
• What is the cause of Hyperuricemia in this patient?
44Namrata Chhabra, M.D.Biochemistry
A. Inhibition of salvage pathway of purine nucleotide biosynthesis
B. Overactive denovo pathway of purine nucleotide biosynthesis
C. Overactive xanthine oxidaseD. Impaired excretion of uric acid
45Namrata Chhabra, M.D.Biochemistry
A) Inhibition of salvage pathway?
PRPP Synthetase
46Namrata Chhabra, M.D.Biochemistry
B. Overactive denovo pathway of purine nucleotide biosynthesis
PRPP Synthetase
47Namrata Chhabra, M.D.Biochemistry
C. Over active Xanthine oxidase ?
PRPP Synthetase
48Namrata Chhabra, M.D.Biochemistry
D. Impaired uric acid excretion ?
49Namrata Chhabra, M.D.Biochemistry
50Namrata Chhabra, M.D.Biochemistry
The correct answer is D-Impaired uric acid excretion
51Namrata Chhabra, M.D.Biochemistry
• Additionally hyperuricemia in chronic alcoholism is also due to some other factors
52Namrata Chhabra, M.D.Biochemistry
Excess purine nucleotide degradation
53Namrata Chhabra, M.D.Biochemistry
High purine content in alcoholic beverages ?
• The higher purine content in some alcoholic beverages such as beer is also an additional factor.
54Namrata Chhabra, M.D.Biochemistry
55Namrata Chhabra, M.D.Biochemistry
• Urea and creatinine are elevated (renal failure)
• Electrolyte imbalance resulting from acidosis and associated renal failure
• Low Hb - Bleeding and associate nutritional deficiencies
• High W.B.C. Count- Sepsis• Low blood pressure -Circulatory failure
56Namrata Chhabra, M.D.Biochemistry
57Namrata Chhabra, M.D.Biochemistry
• Cirrhosis and portal hypertension with bleeding varices and
• Sepsis, resulting in shock, • Lactic acidosis, anemia and• Renal failure.
58Namrata Chhabra, M.D.Biochemistry
59Namrata Chhabra, M.D.Biochemistry
60Namrata Chhabra, M.D.Biochemistry
Implications of excess Acetate
61Namrata Chhabra, M.D.Biochemistry
62Namrata Chhabra, M.D.Biochemistry
63Namrata Chhabra, M.D.Biochemistry
64Namrata Chhabra, M.D.Biochemistry