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Case  discussion

The most probable diagnosis for this patient is Alcohol- related Liver disease. It is not apparent from the history but the patient must had been a hidden alcoholic and had consumed alcohol in excess during his business trip. The points in favor of the diagnosis are as follows-

1)  The levels of transaminases are high

The transaminases are markers of cell necrosis, and in most cases, the serum ALT( Alanine amino transferase) is higher than the AST(Aspartateamino transferase). However, this patient’s serum AST is higher than the serumALT, and his serum GGT (Gamma Glutamyl transpeptidase) is disproportionately elevated over the serum ALP (Alkaline phosphatase). GGT is a marker of alcoholism.  Both ALP and GGT rise in obstructive liver diseases.

This enzyme relationship (GGT high and normal ALP) in this patient is characteristic of alcohol-related liver disease. Alcohol is a mitochondrial poison, and AST is primarily located in the mitochondria, hence it is preferentially elevated over the ALT. Alcohol also induces the synthesis of GGT rather than of ALP. Thus, the patient has alcohol-related liver disease rather than a viral hepatitis or obstructive liver disease.

2) Hypoglycemia- 

Alcohol intake also explains the patient’s hypoglycemia and memory problems. In the metabolism of alcohol, NADH is increased, which results in the reversal of all the normal NAD: NADH reactions,one of which is pyruvate to lactate. Since pyruvate is an intermediate of pathway of gluconeogenesis, its conversion to lactate reduces its concentration, so fasting hypoglycemia may occur. Recall that the brain requires glucose as a fuel; therefore, fasting hypoglycemia results in mental status abnormalities (neuroglycopenia) in these patients.

3) Hyperuricemia –

Hyperuricemia in this patient is likely due to the increase in lactic acid and Beta hydroxy butyric acid (Ketone body) formation. Both these products compete with uric acid for excretion in the proximal tubule, as they share a common transporter. Uric acid is retained while the other two products are excreted.

The synthesis of ketone bodies is increased in alcoholism owing to the increase in acetyl-CoA as the end product of alcohol metabolism and its conversion into ketone bodies by the liver. The increase in NADH  produced from the metabolism of alcohol drives the reaction from acetoacetic  acid to beta hydroxy butyrate.(Acetone , Acetoacetate and beta hydroxybutyrate are the three ketone bodies. Acetoacetate is the primary ketone body,acetone is produced by spontaneous decarboxylation of Acetoacetate, while beta hydroxybutyrate is produced from reduction of Acetoacetate)

Hence, people with alcoholism commonly have two causes for metabolic acidosis: lactic acidosis and ketoacidosis. Approximately 20% of patients with Hyperuricemia will develop gout.

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Case Study-

A 54 -year-old executive reported with vague complaints of fatigue and some alterations in mental status, such as forgetting appointments.  He recalled that the problems had arisen after his visit to abroad few months back on a business meeting. He also complained of some loss of appetite and vague pain especially towards the right side of abdomen.
General physical examination revealed a borderline enlargement of the liver. Important laboratory findings were as listed below:

Serum AST = 320 IU/L –             (Normal 0-41 IU/L)
Serum ALT = 120 IU/L –              (Normal 0-45 U/L)
Serum ALP = 78 IU/L                   (Normal 30-115 IU/L)
Serum GGT = 170U/L                    (Normal 6-37 U/L)
Serum total Bilirubin =-1.1mg/d L (Normal -0.2-1.2mg/dL)
Blood glucose = 58 mg/dL           (Normal 60-100 mg/dL)
Serum uric acid = 10.8 mg/dL    (Normal 3.0-9mg/dL)
 

CBC and urinalysis results were normal.

What is the probable diagnosis?

Comment on the findings

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Case Details
A 65 –year-old man reported with visible Jaundice which he had noticed to be deepening in color. There was no history of pain, fever or any drug intake, but he complained of some weight loss and pales tools from the past few days. He was a moderate drinker. There was no history of such like episode before.
 Blood Biochemistry revealed-
Serum Total bilirubin 20mg/dl
AST-87 U/L
ALT- 92 U/L
ALP-350 U/L
What is the likely diagnosis?
 
Case discussion– In this case, by far the most likely diagnosis is Obstructive Jaundice which might be due to carcinoma of the head of the head of pancreas, obstructing the common bile duct. This classically gives rise to severe, painless, deep jaundice which is in keeping with a Bilirubin of 20 mg/dL. In this case obstructive Jaundice is characterized by high Alkaline phosphatase activity that is more than three times the upper limit of the reference range. The Aspartate and Alanine aminotransferase activities in the given case do not indicate severe hepatocellular damage.
 
 1) The aminotransferase (transaminases) are sensitive indicators of liver cell injury and are most helpful in recognizing acute hepatocellular diseases such as hepatitis. The amino transferases are normally present in the serum in low concentrations. These enzymes are released into the blood in greater amounts when there is damage to the liver cell membrane resulting in increased permeability. Liver cell necrosis is not required for the release of the amino transferases, Levels of up to 300 U/L are nonspecific and may be found in any type of liver disorder. Strikingelevations—i.e., aminotransferase > 1000 U/L—occur almost exclusively in disorders associated with extensive hepatocellular injury such as (i) viral hepatitis, (ii) ischemic liver injury (prolonged hypotension or acute heart failure), or (iii) toxin- or drug-induced liver injury. Inmost acute hepatocellular disorders, the ALT is higher than or equal to the AST. An AST:ALT ratio > 2:1 is suggestive while a ratio > 3:1 is highly suggestive of alcoholic liver disease. In obstructive jaundice the aminotransferases are usually not greatly elevated.
   2) Alkaline phosphatase The activities of three enzymes—alkaline phosphatase, 5′-nucleotidase, and γ-glutamyl transpeptidase (GGT)—areusually elevated in Obstructive liver diseases(Cholestasis). GGT elevation in serum is less specific for cholestasis than are elevations of alkaline phosphatase or 5′-nucleotidase. GGT estimation is done to identify patients with occult alcohol use. The normal serum alkaline phosphatase consists of many distinct isoenzymes found in the liver, bone, placenta, and, less commonly,small intestine.  Elevation of liver-derived alkaline phosphatase is not totally specific for cholestasis,and a less than threefold elevation can be seen in almost any type of liver disease. Alkaline phosphatase elevations greater than four times normal occur primarily in patients with cholestatic liver disorders, infiltrative liver diseases such as cancer  and bone conditions characterized by rapid bone turnover (e.g., Paget’s disease). In bone diseases, the elevation is due to increased amounts of the bone isoenzymes.In liver diseases, the elevation is almost always due to increased amounts of the liver isoenzyme.  In intratrahepatic obstruction values are increased  as in drug-induced hepatitis and primary biliary cirrhosis.Very high values  arefound in Extrahepatic obstructive  due to cancer, common duct stone, or bile duct stricture.The level of serum alkaline phosphatase elevation is not helpful in distinguishing between intrahepatic and extrahepatic cholestasis. Values are also greatly elevated in hepatobiliary disorders seen in patients with AIDS.
  
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Case Study

A 28-year-old man with a long history of intravenous drug abuse and chronic hepatitis B presented with jaundice.Physical examination revealed an anemic, malnourished man with dependent pitting edema and ascites. He had the following profile

A) Blood biochemistry:

1)  Total protein 8.2 g./dL
2)  Albumin 2.6 g/dl
3)  Globulins 5.6 g/dL
4)  Calcium 6.8 mg/dL,
5)  BUN 6 mg/dL
6)  Creatinine 0.9 mg/dL
7)  Total Bilirubin 6.0 mg/dL
8)  AST (Aspartate amino transferase) 200 U/L
9)  ALT (Alanine amino transferase)350 U/L
10)  ALP(Alkaline Phosphatase) 180 U/L
11)    LDH (Lactate Dehydrogenase)300 U/L
12)    CBC: macrocytic anemia with hyper segmented neutrophils, mild neutropenia, and mild thrombocytopenia
13) Prothrombin time (PT) was prolonged and did not correct with intramuscular vitamin K administration.
B) Urinalysis: Positive for Bilirubin
i) What is the clinical significance of his abnormal liver function tests, hypoalbuminemia, and prolonged prothrombin time that does not correct with intramuscular vitamin K?

ii) What is the clinical significance of hypocalcemiain this patient?
iii) Why does he have a low serum BUN?
iv) What is the most likely cause of the macrocytic anemia?

Case discussion

Cause for Abnormal liver function tests
The patient is most probably suffering from chronic end-stage liver disease secondary, most likely, to chronic hepatitis B.

1)  Transaminases
     The transaminases are moderately elevated, and ALT is higher than AST. In acute    hepatitis, the transaminases would be higher owing to the presence of more liver tissue; however, in chronic hepatitis, the lossof hepatocytes and replacement by fibrosis results in less of an increase.
2)   Hypoalbuminemia and a prolonged prothrombin time(PT)are markers of increased severity of liver disease, since both depend on the ability of the liver to synthesize proteins (albumin and coagulation factors).Inability to correct the PT with vitamin K signifies  that the liver is unable to synthesize the precursor vitamin K-dependent factors II, VII, IX, and X for(γ-carboxylation by vitamin K into functional coagulation factors). So the synthetic functions of liver are impaired.
3)   Hypocalcemia- The total serum calcium represents the calcium that is bound to albumin (40%), other anions (13%), and free (ionized calcium; 47%). Low ionized calcium may result in tetany. Therefore, in the presence of hypoalbuminemia, the most common cause of hypocalcemia, the total calcium is decreased while the ionized calcium is normal, so tetany is not present. Hypocalcaemia is partly due to hypoalbuminemia and to hypovitaminosis D secondary to his liver disease. The liver is responsible for the first hydroxylation step in vitamin D metabolism after its reabsorption from the small bowel. Hypocalcemia is a stimulus for secondary hyperparathyroidism, which is likely, to be present in this patient as well.
4)  Low BUN level-owing to location of the urea cycle in the liver, the presence of liver disease seriously hampers the normal function of disposing of ammonia in the urea cycle. Hence, in chronic liver disease, the serum BUN is low while the ammonia level is increased.
5)   Macrocytic anemiaThe macrocytic anemia with hyper segmented neutrophils in this patient is more likely secondary to folate rather than to B12 deficiency owing to the 3- to4-month supply of folate in the liver versus the 6- to 9-year supply of B12.This is easily verified by measurement of serum folate, RBC folate, and B12.
6)  Elevated LDH-The elevated serum LDH is most likely secondary to destruction of the macrocytic RBCs (which contain increased LDH1 isoenzyme) in the bone marrow by macrophages(ineffective erythropoiesis).
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